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College Code: 212 Phone: 2244593NAVYUG EDUCATION SOCIETY’S: SHETH SHREE N.K. MEHTATRUSTM.D. SCIENCE COLLEGENEAR KAMLA PARK, AERODROME ROAD, PORBANDAR-360575.Dr. A.H.BapodraResidence:M.Sc., Ph.D.“Madhusmruti”Associate professor,Behind Paradise Cinema,Chemistry Department, Porbandar- 360575Porbandar-360575.Gujarat-(INDIA).No.Statement under O. Ph.D. 7 of Saurashtra UniversityThe work included in the thesis is my own work under the supervision ofDr. A.H.Bapodra and leads to some contribution in chemistry subsidised by anumber of references.Dt.:Place: Porbandar.(Mayur B. Buddh)This is to certify that the present work submitted for the Ph. D. Degree ofSaurashtra University by Mayur B. Buddh is his own work and leads to theadvancement in the knowledge of chemistry. The thesis has been prepared under mysupervision.Dt.:Place: Porbandar.Dr. A.H.BapodraAssociate professorChemistry DepartmentPorbandar-360575.

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CONTENTSSYNOPSIS…………………………………………………………… 01STUDIES ON SOME COMPOUNDS OF THERAPEUTIC INTERESTIntroduction………………………………………………………………….. 16CHAPTER - 1: STUDIES ON OXADIAZOLESIntroduction…………………………………………………………………... 23Page No.SECTION – 1.1: SYNTHESIS & STRUCTURE ELUCIDATION OF 4-ISOPROPOXY- N'-[(1E) – ARYL) METHYLENE] BENZOHYDRAZIDE.Introduction …………………………………………………………………. 42Spectral studies ……………………………………………………………… 44Experimental…………………………………………………………………. 52.Result and Discussion ……………………………………………………… 359SECTION -1.2: SYNTHESIS & STRUCURE ELUCIDATION OF 2-(4-ISOPROPOXYPHENYL) - 5 - (ARYL) - 1, 3, 4- OXADIAZOLES.Introduction ………………………………………………………………… 55Spectral studies ……………………………………………………………… 57Experimental ………………………………………………………………… 61Result and discussion………………………………………………………… 362References............................................................................................... …. 64CHAPTER - 2: STUDIES ON MANNICHBASES.Introduction…………………………………………………………………... 75SECTION-2.1: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-(4-ISOPROPOXYPHENYL) 3-N-(ARYL) AMINO METHYL -1, 3, 4 OXADIAZOLE -5 (4H) –THIONE.Introduction ... . . . …………………………………………………………… 88Spectral studies………………………………………………………………. 90Experimental…………………………………………………………………. 94Result and discussion………………………………………………………… 365

CHAPTER: - 03 STUDIES ON PYRAZOLINES.Introduction…………………………………………………………………... 103SECTION: 3.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3- DI CHLORO N-(3-SUBSTITUTED STYRYL CARBONYL) BENZAMIDE.Introduction ...………………………………………………………………… 125Spectral studies……………………………………………………………….. 127Experimental………………………………………………………………….. 131Result and discussion………………………………………………………… 368SECTION: 3.2:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO- N- {3-[3-ARYL-1[H] PYRAZOLINE-5-YL} PHENYL] BENZAMIDE.Introduction…………………………………………………………………… 134Spectral studies …………………..................................................................... 136Experimental………………………………………………………………….. 140Result and discussion…………………………………………………………. 371SECTION: 3.3:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N -{3-[3-(ARYL)-1-PHENYL - 1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.Introduction…………………………………………………………………… 143Spectral studies……………………………………………………………….. 145Experimental………………………………………………………………….. 149Result and discussion…………………………………………………………. 374SECTION: 3.4:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N -{3-[3-(ARYL)-1-ACETYL - 1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.]Introduction…………………………………………………………………… 152Spectral studies……………………………………………………………….. 154Experimental…………………………………………………………………. 158Result and discussion………………………………………………………… 377SECTION: 3.5:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DI CHLORO -N– [3-{3-(ARYL) -1- THIOCARBAMIDO-1[H]- PYRAZO LINE – 5 - YL} PHENYL] BENZAMIDE.Introduction…………………………………………………………………… 161Spectral studies……………………………………………………………….. 163Experimental…………………………………………………………………. 167

Result and discussion………………………………………………………… 380References………………………………………………………………….. 170CHAPTER: - 04:- STUDIES ON PYRIMIDINE-2-THIONES.Introduction…………………………………………………………………... 184SECTION: 4.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N –[3-{4-(ARYL)-2-MERCAPTO -1, 4,-DIHYDRO PYRIMIDINE 6-YL}] BENZAMIDE.Introduction…………………………………………………………………… 193Spectral studies……………………………………………………………….. 195Experimental…………………………………………………………………. 199Result and discussion………………………………………………………… 383References…………………………………………………………………… 202CHAPTER: - 05:- STUDIES ON CYANOPYRIDINESIntroduction…………………………………………………………………... 207SECTION: 5.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO-N-[3-(2-AMINO-4-ARYL-3-CYANO PYRIDINE-6-YL)] BENZAMIDE.Introduction……………………………………………………………………. 217Spectral studies………………………………………………………………… 219Experimental…………………………………………………………………… 223Result and discussion………………………………………………………….. 386References…………………………………………………………………….. 225CHAPTER: - 06:- STUDIES ON DIHYDROPYRIMIDINESIntroduction…………………………………………………………………... 232SECTION: 6.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL- [5 - (3, 4 –DIMETHYL)-PHENYL AMINO CARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.Introduction ... . . . …………………………………………………………….. 254Spectral studies………………………………………………………………… 256Experimental…………………………………………………………………... 260Result and discussion……………………………………………………..…… 389

SECTION: 6.2:- SYNTHESIS AND STRUCTURE ELUCIDATION OF N-PHENYL- 4 -ARYL-[5-(3, 4 - DIMETHYL)-PHENYL AMINO CARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.Introduction ... . . . …………………………………………………………….. 263Spectral studies………………………………………………………………… 265Experimental…………………………………………………………………... 269Result and discussion……………………………………………………...…… 392SECTION: 6.3:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5 -(3,4–DIMETHYL)-PHENYL AMINOCARBONYL]–6–PHENYL-1,4-DIHYDROPYRIMIDINE-2(1H)-AMINO.Introduction ……………………………………………………………………. 272Spectral studies………………………………………………………………… 274Experimental…………………………………………………………………… 278Result and discussion………………………………………………………...… 395References………………………………………………………………..…….. 281CHAPTER: -07:- STUDIES ON THIAZOLOPYRIMIDINES.Introduction…………………………………………………………………... 290SECTION: 7.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5 - (3, 4 –DIMETHYL)-PHENYL AMINO CARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-THIONES.Introduction……………………………………………………………………. 321Spectral studies………………………………………………………………… 323Experimental…………………………………………………………………… 327Result and discussion…………………………………………………………… 398SECTION: 7.2:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-ARYLIDENE - 4 (4′-METHOXYPHENYL) - 5 - (3,4-DIMETHYL PHENYLAMINO) CARBONYL - 6-PHENYL -4,7 DIHYDRO THIAZOLO [3,2-α] - PYRIMIDINE 3-ONES.Introduction…………………………………………………………………… 330Spectral studies………………………………………………………………... 332Experimental………………………………………………………………….. 336Result and discussion……………………………………………………..…… 401References……………………………………………………………………... 339

CHAPTER: - 08:- BIOLOGICAL ACTIVITY STUDIES.A) Antimicrobial activity studiesIntroduction…………………………………………………………………... 355Graphical data of in vitro Evaluation of Antimicrobial screening………….. 357B) Antitubercular activity studiesIntroduction…………………………………………………………………... 402Graphical data of in vitro Evaluation of Antimicrobial screening………….. 357Activity Data Table………………………………………………………….. 406

SYNOPSIS

1SYNOPSISSTUDIES ON SOME COMPOUNDSOF THERAPEUTIC INTERESTMAYUR B. BUDDHAUGUST-2009Chemistry DepartmentM.D.Science CollegePorbandar - 360575.Gujarat-(INDIA)

2SYNOPSIS of the thesis to be submitted to the Saurashtra University forthe degree of Doctor of Philosophy in chemistry.Faculty : ScienceSubject : ChemistryTitle : “STUDIES ON SOMECOMPOUNDS OFTHERAPEUTICINTEREST”Name of the Candidate : Mayur B. BuddhRegistration number : 3486Date of Registration : 18 th September, 2006Name of the Guide : Dr. Atul H. BapodraAssociate Professor,Chemistry Department.M. D. Science College,Porbandar -360575.Submitted to : Saurashtra UniversityPlace of workChemistry DepartmentM.D.Science CollegePorbandar- 360575.Gujarat-(India)

3A brief summary of the work to be incorporated in the thesis entitled“STUDIES ON SOME COMPOUNDS OF THERAPEUTIC INTEREST”has been summarized as under.CHAPTER: - 01 STUDIES ON OXADIAZOLES.CHAPTER: - 02 STUDIES ON MANNICHBASES.CHAPTER: - 03 STUDIES ON PYRAZOLINES.CHAPTER: - 04 STUDIES ON PRIMIDINE-2-THIONES.CHAPTER: - 05 STUDIES ON CYANOPYRIDINES.CHAPTER: - 06 STUDIES ON DIHYDROPYRIMIDINES.CHAPTER: - 07 STUDIES ON THIAZOLOPYRIMIDINES.CHAPTER: - 08 BIOLOGICAL ACTIVITY STUDIES.CHAPTER: - 01:- STUDIES ON OXADIAZOLES:The chapter deals with the preparation and structure elucidation of some novelSchiff’s bases and oxadiazoles.A large number of compounds derived from azomethine group have been reported asactive biological entities, where 1,3,4,-oxadiazoles play a vital role owing to their wide rangeof therapeutic activities such as analgesic, anti-inflammatory, antitubercular, antimicrobialetc. Thus considerable interest has been aroused to design the compounds with oxadiazoleheteroycle in search of drug with better improved potential and to studying their therapeuticpotency with several microbes.The constitution of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.

4SECTION: 1.1:- SYNTHESIS & STRUCTURE ELUCIDATION OF 4-ISOPROPOXY-N'-[(1E) – (ARYL) METHYLENE] BENZOHYDRAZIDE.OOC H 3NHCH 3NRCompound - (I)R= ArylThe above compounds were synthesized by the condensation of 4-isopropoxy benzoicacid hydrazide with different aromatic carboxaldehyde in the presence of catalytic amount ofglacial acetic acid.SECTION: 1.2:-SYNTHESIS & STRUCURE ELUCIDATION OF 2-(4-ISOPROPOXYPHENYL) - 5 - (ARYL) - 1, 3, 4- OXADIAZOLES.CH 3NNC H 3OORCompound - (II)R= ArylThe above compounds were synthesized by two routes: Route-1:- oxidativecyclisation of Schiff’s base with potassium permanganate, Route-2:-oxidative cyclisation ofSchiff’s base with chloramine-T in presence of proper solvent and the percentage yield werecompared.

5CHAPTER: - 02:- STUDIES ON MANNICHBASES.The chapter deals with the preparation and structure elucidation of some novelmannichbases.Compound containing bridge N-atom exhibit pronounced pharmacological activities.Mannich base derivatives with bridge N-atom have been found to be potent drug in medicinalscience and possess a wide range of therapeutic activities like antihypertensive,antidepressant, anticholesterinic, antifungal and antibacterial etc. By considering this validobservation, we have synthesized some newer mannich bases, which are described as under.The constitution of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.SECTION: 2.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-(4-ISOPROPOXY PHENYL) 3-N-(ARYL) AMINO METHYL -1, 3, 4OXADIAZOLE -5 (4H) –THIONE.RNHNNC H 3OOSCH 3Compound- (III)R=ArylThe above compounds were synthesized by the condensation of 2-(4-isopropoxyphenyl) -1, 3, 4,-oxadiazole -5(4H)-thione with different aromatic amines in presence offormaldehyde using methanol as a solvent.

6CHAPTER: - 03:- STUDIES ON PYRAZOLINES.The chapter deals with the preparation and structure elucidation of some novelchalcones and their heterocyclic derivatives.Chalcone derivatives signify various biological activities such as analgesic, antiinflammatory,antitubercular, antimicrobial etc. Over and above chalcones are good synthonsfor various organic molecules. This valid observation led us to synthesize some novelchalcones as a synthone for various heterocyclic compounds.The constitutions of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.SECTION: 3.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO N-(3-SUBSTITUTED STYRYL CARBONYL)BENZAMIDE.ClClONHORCompound- (IV)R= ArylThe above compounds were synthesized by the condensation of N-(3-acetylphenyl)-2,3-dichlorobenzamide with different aromatic carboxaldehyde in presence of basic catalyst byusing proper solvent.

7SECTION: 3.2:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO- N- {3- [3-ARYL-1[H] PYRAZOLINE-5-YL} PHENYL]BENZAMIDE.ClClORHNNNHCompound - (V)R= ArylThe above compounds were synthesized by the cyclocondensation of compound(IV) with alcoholic hydrazine hydrate.SECTION: 3.3:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N - {3-[3-(ARYL)-1-PHENYL - 1[H] PYRAZOLINE –5 - YL} PHENYL] BENZAMIDE.ClClORHNNNCompound - (VI)R= ArylThe above compounds were synthesized by the cyclocondensation of compound (IV)with phenyl hydrazine in glacial acetic acid.

8SECTION: 3.4:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N - {3-[3-(ARYL)-1-ACETYL - 1[H] PYRAZOLINE –5 - YL} PHENYL] BENZAMIDE.]ClClHNONRNOCH 3Compound - (VII)R= ArylThe above compounds were synthesized by the cyclocondensation of compound -(IV) with hydrazine hydrate in glacial acetic acid.SECTION: 3.5:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO -N– [3-{3-(ARYL) -1- THIOCARBAMIDO-1[H]-PYRAZO LINE – 5 - YL} PHENYL] BENZAMIDE.ClClHNONRNSNH 2Compound - (VIII)R= ArylThe above compounds were synthesized by the cyclocondensation of compound (IV)with thiosemicarbezide in presence of sodium methoxide using anhydrous methanol.

9CHAPTER: - 04:- STUDIES ON PYRIMIDINE-2-THIONES.The chapter deals with the preparation and structure elucidation of some novelpyrimidine-2-thiones.Pyrimidine-2-thione nucleus possesses notable pharmaceutical importance andgenetic activities, some of their derivatives occur as usual product like nucleic acids andvitamin B. The present popularity of these pyrimidine derivatives are mainly due to theirclose structural relationship to the clinically important calcium channel blockers. This validclarification led us to synthesize some new pyrimidine-2-thiones in search of agents havingbetter therapeutic potency.The constitution of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.SECTION: 4.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N – [3-{4-(ARYL)-2-MERCAPTO -1, 4,-DIHYDROPYRIMIDINE 6-YL}] BENZAMIDE.ClClRONHHNNHSCompound - (IX)R= ArylThe above compounds were synthesized by the cyclocondensation of compound (IV)with thiourea in presence of sodium methoxide using anhydrous methanol.

10CHAPTER: - 05:- STUDIES ON CYANOPYRIDINESThe chapter deals with the preparation and structure elucidation of some novelcyanopyridines.In continuation of our synthetic manipulation about pharmacologically activecompounds, some cyanopyridines possess antibacterial, antifungal, antidiabetic,anticholesterinic and antihypertensive activity. To approach this goal, preparation of somenovel cyanopyridines have been undertaken which are described as under.The constitution of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.SECTION: 5.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO-N-[3-(2-AMINO-4-ARYL-3-CYANO PYRIDINE-6-YL)]BENZAMIDE.ClClROCNHNN NH 2Compound - (X)R= ArylThe above compounds were synthesized by the cyclocondensation of the compound-(IV) with malononitrile and ammonium acetate by using proper solvent .

11CHAPTER: - 06:- STUDIES ON DIHYDROPYRIMIDINESThe chapter deals with the preparation and structure elucidation of some noveldihydropyrimidine derivatives.Dihydropyrimidine derivatives represent one of the most active classes of compoundspossessing a wide spectrum of pharmacological activities such as anti-inflammatory,antiviral, antimicrobial, antitumor, calcium channel blockers, antihypertensive agent andanticancer. This observation prompted us to synthesize newer dihydropyrimidines in searchof better therapeutic agent.The constitutions of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.SECTION: 6.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5 - (3, 4 – DIMETHYL)-PHENYL AMINO CARBONYL] – 6 –PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.H 3 CCORH 3NHNHNHOCompound – (XI)R= ArylThe above compounds were synthesized by multi components biginelli reaction whichinvolves the condensation of N-(3, 4-dimethylphenyl)-3-oxo-3-phenylpropanamide with ureaand aryl carboxaldehydes.

12SECTION: 6.2:- SYNTHESIS AND STRUCTURE ELUCIDATION OF N-PHENYL- 4-ARYL-[5-(3, 4 - DIMETHYL)-PHENYL AMINO CARBONYL] – 6 –PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.H 3 CCORH 3NHNNHOCompound - (XII)R= ArylThe above compounds were synthesized by multi components biginelli reaction whichinvolves the condensation of N-phenyl urea, and N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide and substituted aromatic carboxaldehydes.SECTION: 6.3:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5 -(3,4–DIMETHYL)-PHENYL AMINOCARBONYL]–6 – PHENYL- 1, 4 -DIHYDROPYRIMIDINE-2(1H)-AMINO.H 3 CCORH 3NHNHNHNHCompound - (XIII)R= Aryl

13The above compounds were synthesized by the condensation of N-(3, 4-dimethylphenyl)-3-oxo-3-phenylpropanamide with guanidine hydrochloride and aromaticcarboxaldehyde in presence of basic catalyst and DMF as a solvent.CHAPTER: -07:- STUDIES ON THIAZOLOPYRIMIDINES.The chapter deals with the preparation and structure elucidation of thiopyrimidinesand its fused derivative thiazolopyrimidines.Fused pyrimidines have become of considerable pharmacological interest. Many ofthese compounds have proved to be active anticancer, antipyretic and anti-inflammatoryagents and also exhibited modest activity against gram positive bacterial strains. Incontinuation of our interest in the chemistry of fused pyrimidines, we would like to reportsome new synthesized compounds.The constitution of newly synthesized and purified compounds have been delineatedby elemental analysis, IR, PMR & mass spectral studies. Purity of all compounds have beenchecked by thin layer chromatography using precoated silica gel plates and appropriatesolvent system.SECTION: 7.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5 - (3, 4 – DIMETHYL)-PHENYL AMINO CARBONYL] – 6 –PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-THIONES.H 3 CH 3 CNHORNHNHSCompound - (XIV)R= Aryl

14The above compounds were synthesized by multicomponent biginelli reaction whichinvolves the condensation of N-(3, 4-dimethylphenyl)-3-oxo-3-phenylpropanamide withthiourea and aryl carboxaldehydes.SECTION: 7.2:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-ARYLIDENE- 4 (4′-METHOXYPHENYL) - 5 - (3,4-DIMETHYL PHENYLAMINO)CARBONYL - 6-PHENYL - 4,7 DIHYDRO THIAZOLO [3,2-α] -PYRIMIDINE 3-ONES.C H 3OH 3 CCOOH 3NHNNSRCompound - (XV)R= ArylThe above compounds were prepared by the condensation of compound-(XIV) withchloroacetic acid, sodium acetate and different aromatic carboxaldehydes in presence ofglacial acetic acid and acetic anhydride.

15CHAPTER: - 08:- BIOLOGICAL ACTIVITY STUDIES.The chapter deals with the biological activity studies of purified compounds describedin chapter 1 to 7.The purified organic compounds have been screened for their in vitro Antibacterialactivities against Gram positive bacterial strain like S.aureus and S.pyogenus and Gramnegative bacterial strain like E.coli and P.aeruginosa and Antifungal activities againstfungal strains like C.albicans, A.niger, and A.clavatus. at different concentrations and MIC(Minimum Inhibitory Concentration) were also determined using broth dilution method.The antimicrobial activities of synthesized compounds have been compared withstandard drugs like Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin andNorfloxacin for antibacterial and Nystatin and Greseofulvin for antifungal activities. Selectedcompounds have also been sent for Antitubercular activity studies.

STUDIES ON SOMECOMPOUNDS OFTHERAPEUTIC INTEREST

Studies on some compounds… 16STUDIES ON SOME COMPOUNDS OF THERAPEUTIC INTERESTThe primary objective of medicinal chemistry is the design and discovery of newcompounds that are suitable for use as drugs. This process requires a team effort. It not onlyinvolves chemists but also workers from a wide range of disciplines such as biology,biochemistry, pharmacology, computing and medicine amongst others. The brief introductionregarding studies on therapeutic interested compounds (drugs) is as under.(A) Drug:The word drug is derived from the French word “drogue” which means ‘a dry herb’. Itis the single active chemical entity present in a medicine that is used for diagnosis,prevention, treatment / cure of a disease. This disease oriented definition of drug does notinclude contraceptives or use of drugs for improvement of health. According to “WHO” adrug may be defined as “Any substance or product which is used or intended to be used formodifying or exploring physiological system as pathological status for the benefit of therecipient”.(B) Pharmacology:Pharmacology is the science of drugs. In a broad sense, it deals with interaction ofexogenously administered chemical molecules (drugs) with living system. It encompasses allaspects of knowledge about drugs, but most importantly those that are relevant to effectiveand safe use for medicinal purposes. For thousands of years most drugs were crude naturalproducts of unknown composition and limited efficiency. Only the over effects of thesesubstances on the body were rather imprecisely known, but how the same were produced wasentirely unknown. Over the past 100 years or so, drugs have been purified, chemicallycharacterized and a vast variety of highly potent andselective new drugs has been developed.The two main divisions of pharmacology are pharmacodynamics and pharmacokinetics.(a) Pharmacodynamics : It is derived from the Greek word “dynamic”means power. Whatthe drugs does to the body? This includes physiological and biochemical effects of drugsand their mechanism of actionat macromolecular / sub cellular organ systems.General Intro…

Studies on some compounds… 18countries) should concentrate on these drugs by identifying them as Essential Drugs. The“WHO” has laid down criteria guide selection of an essential drug :(I) Adequate data on its efficiency and safety should be available from clinical studies.(II) It should be available in a form in which quality, including bioavailability and stability onstorage can be assured.(III) Its choice should depend upon pattern of prevalent diseases; availability o f facilities andtrained personnel; financial resources; genetic, demographic and environmental factors.(IV) In case of two or more similar drugs, choice should be made on the basis of their relativeefficiency, safety, quality, price, availability and cost benefit ratio should be a majorconsideration.(V) Choice may also be influenced by comparative pharmacokinetic properties and localfacilities for manufacture and storage.(VI) Most essential drug should be single compound.Fixed ratio combination products should be included only when dosage of each ingredientmeets the requirements of a defined population group, and when the combination has aproven advantage.(VII) Selection of essential drug should be a continuous process which should take intoaccount the changing priorities for public health action, epidemiological condition as well asavailability of better drugs/ formulations and progress in pharmacological knowledge.(C) Drug Development:Many natural products by trial and error, came into practise for combating humanailments existent during early human observation. With the advent of modern scientificapproach, various plant medicines came underchemical scrutiny, ultimately leading to theisolation of active principles sincerely.Such compounds either in extract form or in pure form became a part ofpharmacopoeias. For instance, though the Chinese drug, Mauhang was in use for over 5000years for the treatment of various types of fever and respiratory ailments, its active principle,Ephidrine was isolated in 1887. In 1925 chemical investigations followed by pharmacologicalevaluation led this compound into the modern medicine. Similarly during this period, ureastibamine was introduced as the first drug in 1920 for the treatment of Kala-azar. In 1930, DeRauwolfia preparation were first employed for sedative and hypotensive properties. A drug isa substance having abnormal effect on certain body functions eg. Strychnine stimulates theaction of heart and aspirin retards its action. Since both of them effects abnormally, the twoGeneral Intro…

Studies on some compounds… 19substances are known as drugs. Chemical sciences contributed extensively new discoveriesleading to useful drugs since after 1930. The modern concept of drug discovery started in1933 by Gerhand Domagk with his finding of “Prontosil Red”, a compound responsible forthe antibacterial activity. The advent of sulphonamides drew the attention for the differentactivities of various chemicals for bacterial and human cells, this important factor promptedFlorey and Chain in 1939 to investigate penicillin which was discovered ten years earlier byAlexander Fleming. The spectacular chemotherapeutical properties of penicillin and itsdramatic war-time development for the treatment of wounds made penicillin, a mostcommonly used inexpensive drug. A large number of important drugs have been introducedduring the period of 1940 to 1980. This period is known as “Golden period” of new drugdiscovery. Thus starting from 1933 - the first antibacterial drug prontosil leading to varioussulpha drugs ; 1940 – penicillin ; 1945 – chloroquine – antimalarial ; 1950 – Methyldopa– anti-hypertensive; 1967 – chlorothiazine -diuretic; 1958 - adrenergic beta blockerscoronary vasodilatory; 1960 – semi synthetic penicillin -antibacterial; 1965 -trimethoprimantimicrobial;1967-disodium chromoglycoate - antiallergic; 1972 - cimetidine H2–antagonist; 1975 -verapamil- calciumantagonist and 1981 - captopril - antihypertensive.There are some specific examples representing new therapeuticagent eg. Metormineglipizide-anti diabetic.(D) Latest Drug Developments:The current interest in the creation of large, searchable libraries of organic compoundshas captured the imagination of organic chemists and the drug discovery community. Innumerous laboratories the efforts are focused on the introduction of chemical diversity, whichhave been recently reviewed and pharmacologically interesting compounds have beenidentified from libraries of widely different compositions.The process of drug design is extensively driven by the instinct and experience ofpharmaceutical research scientists. It is often instructive to attempt to “capture” theseexperiences by analyzing the historical record that are successful drug design projects of thepast. From this analysis, the inferences are drawn which play an important role in shaping ourcurrent and future projects. Towards this region, we would like to analyse the structures of alarge number of drugs - the ultimate product of a successful drug design effort. Our goal forthis is to begin to deconvolute this information in order to apply it to design of new drugs.General Intro…

Studies on some compounds… 20Different kinds of drugs are developed for different types of diseases viz. which canbe defined with their names of the modern drugs are as under.(a) Anticancer drugsThe drugs, which stops the abnormal growth of cell tissues in human body, are termedas anticancer drug. Vinblastin and Busulphan are the novel anticancer drugs.(b) Hepatoprotective drugsDrugs, which gives vitality to liver and protects liver by giving immunity poweragainst antibodies, are termed as Hepatoprotective drug.(c) Antimalarial drugsDrugs, which kills the plasmodium causing malaria are called antimalarial drug.Combination of Sulphamethoxazole with Pyrimethamine is a novel antimalarial drug.(d) Drug for meningitisDrugs, which cures the inflammation of meningitis, are termed as meningitis drugsCifalexin is a novel meningitis drug.(e) Drug for typhoidDrugs, which kills the bacteria of Salmonella typhi causing typhoid are known astyphoid drugs. A novel drug for typhoid is Ciprofloxacin.(f) Antidiabetic drugsDrugs, which converts the excess glucose of blood into glycogen are termed asantidiabetic drugs. Novel antidiabetic drugs are Metformin, Glipizide and Gliclazide.(g) Antitubercular drugsDrugs, which kills the bacteria of mycobacterium tuberculosis and thus cures lesionsof pleural cavity. A novel antitubercular drug is Ethambutol.(h) Antiasthamatic drugsDrugs, which prevents the attack of asthama and gives relax respiration are calledantiasthamatic drugs. Novel antiasthamatic drugs are Ethophylline, Theophylline andAsmon.General Intro…

Studies on some compounds… 21(i) Antihypertensive drugsDrugs, which normalizes the blood pressure by dilating blood vessels are calledantihypertensive drugs. Novel antihypertensive drugs are Atenolol, Amlodipine andNifedipine.(j) Anti-AIDS drugsDrugs, which kill the viruses of AIDS i.e., HIV-1 and HIV-2, are called anti-AIDSdrugs. Novel drugs are Zidovudine, Acyclovir and Didanosine.The ultimate product of a successful drug design effort. Our goal for this is to begin todeconvolute this information in order to apply it to design of new drugs.AIMS AND OBJECTIVESIn the pharmaceutical field, these have always been and will continue to be a need fornew and novel chemical inhibitors of biological function. Our efforts are focused on theintroduction of chemical diversity in the molecular fram work in order to synthesizingpharmacologically interesting compounds of widely different composition.During the course of our research work, looking to the application of heterocycliccompounds, several entities have been designed, generated and characterized using spectralstudies. The details are given as under.1. To synthesize therapeutically active compounds like Schiff’s bases, oxadiazole ,mannichbases, pyrazolines, cyanopyridines, thiopyrimidines, dihydropyrimidines andthiazolopyrimidines.2. To characterize these products for structure elucidation using several spectroscopictechniques like IR, PMR and Mass spectral studies.3. To assess the reaction and purity of the compounds were done by TLC.4. To evaluate these products for better drug potential against different strains ofbacteria and fungi.General Intro…

Studies on some compounds… 22In view of these facts, the research work presented in thesis is as follows.CHAPTER: - 01 STUDIES ON OXADIAZOLES.CHAPTER: - 02 STUDIES ON MANNICHBASES.CHAPTER: - 03 STUDIES ON PYRAZOLINES.CHAPTER: - 04 STUDIES ON PRIMIDINE-2-THIONES.CHAPTER: - 05 STUDIES ON CYANOPYRIDINES.CHAPTER: - 06 STUDIES ON DIHYDROPYRIMIDINES.CHAPTER: - 07 STUDIES ON THIAZOLOPYRIMIDINES.CHAPTER: - 08 BIOLOGICAL ACTIVITY STUDIES.General Intro…

CHAPTER - 1STUDIES ONOXADIAZOLES

Studies on some compounds… 23INTRODUCTIONAzomethine derivatives have been found to be potent drug in pharmaceuticalindustries and possess a wide spectrum of biological activity. Azomethines are alsoknown as Schiff’s base and they are well known intermediates for the preparation ofoxadiazoles, azetidinone, thiazolidinone, formazone, arylacetamide and many otherderivatives. These are the compounds which contain characteristic -C=N group. D. R.Dabideen et al. 1 have prepared Schiff’s base (I) containing indole moiety as potentinhibitors of macrophage migration inhibitory factor proinflammatory activity.HOHNN(I)MeOOAzomethines were discovered by Hugo Schiff 2 by the condensation ofcarbonyl compounds with primary amines in presence of acid catalyst in 1864.However, it is more convenient to work in a solvent such as alcohol, dilute acetic acidor glacial acetic acid. Sometime the reaction is aided by trace of acid, in other casesthe hydrochloride of the amines can be used in the synthesis.In general Schiff’s bases do not react further with either of the reagents usedin their preparation as do most of the other types of simple intermediates.SYNTHETIC ASPECTAzomethine derivatives can be prepared by various methods, which are describedas under.1. General account of the summary of reaction of aldehydes with amine(aromatic or aliphatic) has been reviewed by Murray 3 .R CHO+ R' NH 2 R CH N R'Oxadiazoles…

Studies on some compounds… 242. Strache 4 and Van Alphen 5 have prepared imine involving in two steps.(a) Addition of the amine to the carbonyl group of the aldehyde gives aldol. Thealdol is rarely capable of isolation.R CHO R' NH 2 R CHOHNHR'(b) The loss of water to give an imine (azomethine), this corresponds to the“crotonaldehyde stage” of the aldol condensation.3. Oddo and Tognacchini 6 have introduced the comparative rates of formation ofSchiff’s base from aniline; substituted aniline and aromatic aldehyde using acryoscopy method follow the course of reaction.4. P. L. Beaulieu and co-workers 7 have synthesized (E)-N-phenyl methylene glycineethyl ester by the cyclocondensation of glycine ethyl ester hydrochloride, t-butylmethyl ether (TBME), benzaldehyde was added followed by anhydrous Na 2 SO 4and triethylamine.HCl.N H 2phCHO / Et 3 NCOOEtNa 2 SO 4 / TBME / 48 HrsNCOOEt5. Amanda J. Gallant et al. 8 have prepared Schiff’s bases by condensation ofequimolar quantity of 3,6 diformyl catechol and substituted o-phenylenediamine.OORNH 2OOHOH+N H 2NH 2OROOHOHNOROR6. Nataliya E. Borisova et al. 9 have demonstrated metal-free methods in the synthesisof macrocyclic Schiff’s bases by the condensation of 2,6-dicarbonyl derivatives ofphenols and thiophenols with diamines in the presence of acid.Oxadiazoles…

Studies on some compounds… 257. Ina Bolz et al. 10 have reported novel Schiff’s bases (II) derived from 5- aminobarbituric acid with para-nitro and para-N,N-dimethylamino cinnamaldehyde inethanol.OHNONR 1 NO (II)R 28. H. S. Joshi et al. 11 have synthesized several Schiff’s bases (III) from 4-amino-5-(3-pyridyl)-4H-1,2,4-triazol-3-thiol and different aryl aldehyde by using glacialacetic acid as a catalyst.NNSHNNSHNNNH 2NN+ R CHO gl.CH 3 COOH N(III)R=ArylR9. Takanori Tanaka et al. 12 have developed new chiral Schiff’s base (IV) as a catalystfor the enantioselective addition of diethyl zinc reagents to aldehydes.R 2NH 2R 1+t-Bu OHR 2R 1NOHt-BuOOHR 1 =Me,EtR 2 = i-Pr, t-BuOH(IV)Oxadiazoles…

Studies on some compounds… 26MECHANISMOOH + NH 2 R 1+H2 NR 1+H2 NR 1RR+ROHR+ OH2HHHH- H 2 ORH + -H +R 1RH +2 OHN + HHNR 1THERAPEUTIC IMPORTANCESchiff bases exhibit a wide range of pharmacological activities like antifungal,antibacterial, antiviral, anti-inflammatory etc. B. Shivarama Holla et al.13 haveprepared some new Schiff’s bases having anticancer activity. Ravindra V. Chambhareet al. 14 have prepared some azomethine and tested for their antimicrobial activity.Yadav Bodke and S. S. Sangapure 15 have synthesized some azomethine andtested for their biological activity. Pawar et al. 16 have synthesized azomethine by thecondensation of iodovanillin with different substituted aromatic amines, anddetermined antibacterial activity.N. Raman and co-workers 17 have prepared Schiff’s bases of 4-aminoantipyrine and reported as antimicrobial activity. R. Nair et al.18 have prepared some4-ethyl-6-{(E)-1- [3-arylimino] ethyl} benzene-1,3-diol derivatives (I) fromresacetophenone and reported their antibacterial activity.HOOHH 5 C 2CH 3NRR=m-nitro-ph, o-nitro-ph (I)Oxadiazoles…

Studies on some compounds… 27Mehta R. H. et al. 19 have synthesized coummarin Schiff’s base derivatives of(II) and examined for their antibacterial activity. Khalafallah A. K. and Hassan M.E. 20 have prepared some styryl Schiff’s bases derivatives as potential antibacterial andantifungal activity. Sharaf El-Din, and Nabaweyal21 have synthesized someazomethine Derivatives (III) having good antibacterial activity.HNOORNMe(II)(III)OHD. R. Shekawat et al. 22 have reported in an earlier communication thesynthesis and study of Schiff’s bases from substituted benzaldehyde N-mustards andvarious aryl amines. A number of compounds from this series displayed significantactivity against dunning leukemia (solid), lymphoid leukemia (L1210), and walkercarcinosarcoma (256) (intramuscular). S. Ren and co-workers 23 have reportedsynthesis, biological evaluation, and quantitative structure-activity relationshipanalysis of new Schiff’s bases of hydroxy semicarbazide as potential antitumoragents. M. A. Castro et al. 24 have synthesized Schiff’s base (IV) from pedophilicaldehydes and aliphatic, aromatic and heterocyclic primary amines, all of themmaintained the main biological property the cytotoxic selectivity against the HT-29cell line.RONR'OCOOMeR = H, OCH 3R' = Het.aryl(IV)H 3 COOCH 3OCH 3Oxadiazoles…

Studies on some compounds… 28Chohan et al. 25 have synthesized azomethines, which have been screened andcompared for their antibacterial action against bacterial species Escherichia coli,Pseudomonas aeruginosa and Klebisella pneumonias. Das Joydip 26 have synthesizedtrans-N-refinylidene-n-butylamine (V) which found stabilized in liposome ofphosphatidylcholine. The rate of formation of the Schiff’s base is found to decreasewith increasing cholesterol concentration in the membrane. Patel V. M.27 havesynthesized some new Schiff’s bases having good antibacterial activity.MeMeMeMeNBut(V)Lei Shi et al. 28 have confirmed synthesis and antimicrobial and antifungalactivities of Schiff’s bases derived from 5-chlorosalicylaldehyde and primary amines.Schiff’s bases also shows excellent fluorescent properties which is reported bydifferent chemists. 29-31Schiff’s bases are also utilized as starting material in thesynthesis of industrial. 32 and biological compounds such as â-lactams. 33 S. Samadhiyaet al. 34 have prepared some Schiff’s bases and reported as herbicidal and pesticidalactivities. J. Jyh-Jia et al. 35 have synthesized a series of chemically modified arylaldehydeSchiff’s bases and tested for their antioxidant activity and radiationprotection. J. Parikh and co-workers 36 have demonstrated some 4-[(arylidene) amino]benzoic acid and screened as potential antibacterial agents against bacteria and fungiusing the Agar Ditch method. Palwinder Singh et al. 37 have reported syntheses andanti-cancer activities of 2-[1-(indol-3-yl)-but-3-enylamino]-2-phenyl-ethanols (VI).REtOOCNN(VI)HR= H, ClOxadiazoles…

Studies on some compounds… 29Deshmukh M. D. and Doshi A. G. 38 prepared some new Schiff’s bases showinggood antimicrobial activity against test organism S. aureus, E. coli, Saigella dysentryand Salmonella typhi. Wang and Yangang 39 have synthesized diazomethines havingplant hormone activity. Das Arima et al. 40 have prepared Schiff’s bases ofaminohydroxyl guanidine (SB-AHG5) and tested for antiviral activity against HerpesSimplex virus (HSV-1) and adenovirus (Ad-5) along with eleve other heterocyclicSB-AHG5.Pawar R. P. et al. 41 have synthesized azomethines by the condensation ofiodovanillin with different substituted aromatic amines and tested for antibacterialactivity. Ergenc and co-workers 42 have synthesized azomethine derivatives havingantifungal activity. Yadav Bodke 43 have synthesized some azomethines and tested fortheir biological activity. B. Shivarama Holla et al.44 have prepared and reportedanticancer activity of some new Schiff’s bases.Cascaval Alexandru et al. 45 have synthesized azomethines, which have goodanalgesic and antipyretic properties. Pandeya S. N. et al. 46 have synthesized Schiff’sbases showing good activity against Vibrio cholerae non-O., Shigella boydii,Enterococcus faecalis and Edwaredsiella torla with MIC in the rang of 10-25 μg/ml.Some compounds were found to be active against Salmonell typhi and Vibrocholerae-0, (MIC 25-150 μg/ml).Ali Yousif et al. 47 have synthesized some Schiff’s base derivatives of glucosecontaining acetylenic bond and tested for their bactericidal activity against E. coli andStaphylococcus aureus.Ravindra V. Chambhare et al. 48 have prepared some azomethines and testedfor their antimicrobial activity. B. Shivarama Holla et al.49 have synthesizedazomethines of (VII) having antibacterial and anti-inflammatory activity.ClNNHNORClSCl(VII)R= 4-NO 2 , 2-NO 2 , 4-BrOxadiazoles…

Studies on some compounds… 30Ram Tilak et al. 50 have synthesized some Schiff’s bases, thiazolidinones 4 -triazolines, and formazones of 2-chloro phenothiazines and screened againstcarrageen induced edema in albino rats. The thiazolidinones showed promising antiinflammatoryactivity.S. K. Sridhar et al. 51 and R. Mladenova et al. 52 have separately synthesizedsome Schiff’s base derivatives and reported as antibacterial agents. P. Panneerselvamet al. 53 and S. N. Pandeya et al. 54-55 have been separately prepared some schiff’s basederivatives and reported as antifungal agent. M. N. Ibrahim et al. 56 have reportedsynthesis and use of Schiff’s bases as fluorimetric analytical reagents. V. Alagarsamyet al. 57have been reported some Schiff’s base bearing quinazolin nucleus asanalgesics and anti-inflammatory agents. S. B. Desai et al. 58 and P. Pathak et al. 59have separately reported Schiff’s bases as anticancer agents. K. Vashi et al.60 havesynthesized a series of 2'-hydroxy-3'-chloro-5'-ethyl-N-(p-tolyl)-chalconimines andscreened for their antibacterial activity against Staphylococcus aureus and Escherichiacoli. Michael J. Hearn et al. 61 have prepared isoniazide Schiff’s bases and evaluated asantitubercular activity against Mycobacterium tuberculosis. S. N. Pandeya et al. 62have reported synthesis, antibacterial, antifungal and anti-HIV activity of Schiff’sbase of isatin with N-[6-chlorobenzothiazol-2-yl] thiosemi carbazide.From above importance of Schiff’s bases we also studied the methyl-N-arylamines by reduction of Schiff’s base. From literature survey it is proved that thesederivatives have different variety of biological activities such as P2X7 receptorantagonists, 63 HDM2- p53 protein-protein antagonists, 64 MCH1 receptor antagonist, 65NPY5 antagonists, 66 dual Atk1/2 inhibitors, 67 Selective (VIII) dopamine D3receptors, 68 antiobesity (IX) and antidiabetic. 69OHO(VIII)NHOCH 3NNMeO 2 SNHHO(IX)NHOCHF 2Oxadiazoles…

Studies on some compounds… 31Several methodologies are also reported for the synthesis of methyl-N-arylamine derivatives like, Diels-Alder reaction, 70 carbonylation/intramolecularamidation, 71 phenol Ugi-Smiles condensation, 72 based-induced cyclization, 73 andStaudinger/aza-Wittig reaction, 74 by using bifunctional reagents in MCRs, 75,76 byUllmann-Goldberg coupling 77 by using transmetallating agents such astriarylbismuth, 78 aryllead triacetates, 79 arylboronic acids, 80,81 hypervalent arylsiloxanes. 82Looking to the interesting properties of azomethines, we have synthesizedsome new azomethines, which have been described as under.SECTION-1.1: SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ISOPROPOXY-N'-[(1E)–(ARYL) METHYLENE] BENZOHYDRAZIDE.Oxadiazoles…

Studies on some compounds… 32INTRODUCTION:Thermally stable neutral aromatic 1,3,4-oxadiazoles 83 have been known forabout 80 years. They have been subjected to intensive investigation particularly in thelast decade because of their broad spectrum of uses as biologically active compoundsin medicine, agriculture and dyestuff industries. 1,3,4-oxadiazoles also have beenuseful in diverse areas like drug synthesis, heat resistant ad UV absorbing polymers.The literature prior to 1965 is surveyed in comprehensive reviews 84-86 . The moiety isrepresented by the structure (I).NNRO(I)R'2,5 di substituted 1,3,4-oxadiazole and its derivatives constitute an importantclass of heterocyclic compounds. Due to their remarkable biological activity, likeanticancer 152 , antimicrobial 153 , antimalarial 154 , anticonvulsant 155 , anti-inflammatory 156 ,anti-HIV-1 157 , 1, 3,4-oxadiazole and its derivatives have been frequently employed indrug synthesis, various commercial and industrial applications. In fact 1,3,4-oxadiazole ring carrying substitution in an appropriate position and substituent with anucleophillic centre, are excellent precursors for further synthesis of five and sixmembered heterocycles. A detailed account of biological activities, syntheticusefulness is described in this section.The work presented in the current section is concerned with the synthesis,characterization and antimicrobial activity studies of some novel 1,3,4-oxadiazoles.SYNTHETIC ASPECTS:Different methods for the preparation of 1,3,4-oxadiazole derivatives knownin literatures are as follows.Oxadiazoles…

Studies on some compounds… 331. From N, N’- diacyl hydrazines:The common synthetic approaches to the oxadiazoles involvecyclization of diacyl hydrazines. A variety of reaction conditions andanhydrous reagents as mentioned below, have been used to induce cyclizationof N-N’diacylhydrazines to their respective 1,3,4-oxadiazoles (I). The generalreaction is represented below.OONNRCNH NH CR'RO(I)R'(a)(b)(c)(d)Iodobenzene has been found to be an excellent reagent for the oxidation of avariety of hydrazines to N,N’-diacyl hydrazines which undergo readilycyclization to yield 1,3,4-oxadiazoles. 87A novel and efficient means of affecting the cyclodehydration of N,N’-diacylhydrazines is reported by Brain and coworkers 88 by using polymer supportedburgess reagent in combination with single mode microwave heating.Pd-catalyzed cyclization of N,N’-diacylhydrazines is successfully done byLutuns and his coworkers. 89N, N’-diacylhydrazines on reaction with bissylyl (Me 2 SiCl 2 ) in the presence oftraffic acid catalyst have been reported 90 to yield 1,3,4-oxadiazoles.2. From aldehydes:(a)Aldehydes have been used with trichloroacetic acid hydrazide in the presenceof a base to yield 1,3,4-oxadiazoles 91 (II).ORH+ Cl 3C C NH N CH RO(Base)Cl 3CN NO(II)ROxadiazoles…

Studies on some compounds… 343. From trichloromethylarenes 92Symmetrical 2,5- diaryl-1,3,4-oxadiazoles (III) have been prepared bymaking use of trichloromethylarenes with excess of hydrazine hydrate inalcohol with 68-98% yield.ArCCl 3NH 2 NH 2EtOHArN NArO(III)4. From Acid Hydrazide:Four different routes from acid hydrazides are known to lead theformation of 1,3,4-oxadiazoles.(a) N-acylhydrazines are known to react with orthoformic ester to yieldintermediate imino derivatives, which are at correct oxidation level to cyclizedirectly to the respective 1,3,4-oxadiazoles 93 (IV).RC ONHNH 2(R'O) 3 CHORCNHNCHOR'RN NO(IV)OR'(b)Ladva 94 and his coworkers have utilized the reaction of acid hydrazides witharomatic acids in the presence of phosphoryl chloride. This lead to theformation of corresponding 2,5-disubstituted-1,3,4-oxadiazoles (V).RONHNH 2ArCOOHPOCl 3RN NArO(V)(c)Chloroacetic acid reacts with phenol to give phenoxyacetic acid. This acidafter Conversion to phenoxy acetic acid hydrazide has been cyclized in thepresence of cyanogen bromide to give 2-amino-5-substituted-1,3,4-oxadiazole 95 (VI).Oxadiazoles…

Studies on some compounds… 35OOH+ClOOHNH 2 NH 2ONH NH 2BrCNONN(VI)ONH 2(d) Carboxylic acid hydrazides 96 when treated with carbon disulphide in thepresence of potassium hydroxide in ethanol, yielded 5-substituted-2-mercapto-1,3,4- oxadiazoles (VII).ROCNHNH 2CS 2KOHRN NO(VII)SH(e)Lee et al. 97 have reported the synthesis of 1,3,4-oxadiazoles (VIII) havingphenol or thiophenol group. This was achieved by the treatment of suspensionof salicylic acid hydrazide in toluene with acetic anhydride in the presence ofequimolar methansulfonic acid.OCNH NH 2XHX= O, SMeSO 3 H/TolueneAc 2 O/ reflux 2-9 hrsOrRCOClN NOXH(VIII)R5. From heterocyclic estersDue to biological importance of pyridazines and 1,3,4-oxadiazoles.E.A.Bakhite and coworkers 98 synthesized derivatives containing both the entities inone molecule. Treatment of ethyl-5-hydroxyl-3,4-diphenylthieno [2,3-c]pyridazine -6-Oxadiazoles…

Studies on some compounds… 36carboxylate with hydrazine hydrate in ethanol to carbohydrazide. Furthermore,refluxing of carbohydrazide in glacial acetic acid resulted in the formation of thecorresponding 1,3,4-oxadiazole (IX).PhNPhNPhNPhNSOHSOHR=OEt or PhCOOEtONHN 2H 4.H 2ONRPhAcOHReflux 3h-EtOHNPhNNPhNSOHCONHNH 2OHPh N NS(IX)OCH(OEt) 2or PhCHOR6. From Di(benzotriazole-1-yl)methanimineA.R. Katritzky and coworkers 99 synthesized 2-amino-5- phenyl-1,3,4-oxadiazole (X) by the reaction of benzene carbohydrazide with di(benzotriazol-1-yl)methanimine in THF.NH+ PHCONHNH 2Bt BtDi(benzotriazole-1-yl)methanimineN N(X)NH Ph O 22-Amino-5-phenyl-1,3,4-oxadiazole7. From Trichloroacetic Acid hydrazonesEl kaim and coworkers 100 developed novel route for the synthesis of new1,3,4,-oxadiazoles (XI) from hydrazones. This was achived by the reaction of 4-nitrophenol trichloro acetate with hydrazine and in situ tapping with carbonyl derivative.This was followed by the treatment of these hydrazones with potassium carbonateunder phase transfer conditions to new 1,3,4-oadiazoles.Oxadiazoles…

Studies on some compounds… 37HO 2NOONH 2 NH 2OCCl 3R CR 1RNR 1OCCl 3KN N2CO 3, TEBADioxane, reflux 2 hrs R CHClO2(XI)8. Microwave Assisted Oxidation of 1-Aryl-2-aroylidine hydrazinesSynthesis of 2,5-di substituted-1,3,4-oxadiazoles (XII) by oxidation of 1-aroyl-2-arylidene hydrazines under microwave irradiation using potassiumpermanganate and mixture of acetone/water has been reported by S.Rostamizadeh andcoworkers. 101R 1OCNHNH 2+OR 2CHSiO 2 , HR 1OCNHNCHR 2KMnO 4 , SiO 2Acetone/WaterM.W.I.NNR 1OR 2 (XII)THERAPEUTIC IMPORTANCE2,5-Disubstituted 1,3,4-oxadiazole derivatives have been tested for variouspharmacological properties, which have been summarized in following sections:1. Antitubercular 102-1032. Antimalarial 1043. Hypnotic and sedative 1054. Antithrombic 1065. Anticonvulsatant 1076. Hypoglycemic 1087. Anti-inflammatory 109-1108. MAO inhibitor 1119. Bactericidal 112-113Oxadiazoles…

Studies on some compounds… 3810. Antitumor 11411. Anticancer 11512. Anti-HIV-1 11613. Nematocidal 11714. Herbicidal 118-11915. Antihypertensive 120Beriger Ernst 121 have synthesized a series of oxadiazoles bearing substitutedfuran ring system and reported them as nematocides. A variety of oxadiazoles havebeen synthesized and assessed for their anti-inflammatory 122 , antihypertensive andvirucidal activity. 159 Kazunori Oono et al. 123 have prepared 2,5-disubstituted 1,3,4-oxadiazoles (I) as anxiolytics and anticonvulsants. Andotra et al. 124 have preparedsome 2-amino -1,3,4-oxadiazoles as antibacterial agents. Antipyretic, antiinflammatoryand analgesic activities of 1,3,4-oxadiazoles have been reported 125 .Moreover, in vitro pesticidal activity has been found in compound (II) havingoxadiazole nucleus.NNR2NHOO(I)R 1HNNON NO(II)R2-Amino -1,3,4 – oxadiazoles act as muscle relaxant 126 and showedantimicotic activity. 127 Eduardo Cortes et al. 128 have synthesized some 5-methyl -4H-1-(p-R1-phenyl)-3a, (p-R2-phenyl)-3a, 4- dihydro [1,2,4] oxadiazole [4,5-a] [1,5]Oxadiazoles…

Studies on some compounds… 39benzodiazepines to confirm its pharmacological activity as an anticonvulsant drug(III).R 2HNOR 1N(III)NHSCH 3Moreover B. shivarama Holla et al. 129 have also synthesized 1,3,4- oxadiazolesderivatives (IV) and tested for antibacterial activity.NNN N ORN N (IV)NNOO(CH 2 ) 2ORSulabh Sharma and coworker 130 have reported the anti-inflammatory activityof some new 1,3,4- oxadiazole derivatives (V).COOHNNNNCOCH 3Br NH O(V)NHRJ. C. S. Kataky 131 have reported 2-amino [4-(5-(2-chlorophenyl)-1,3,4-oxadiazole)-2-yl] 6-aryl/substituted aryl -7-oxo-6,7- dihydro thiazolo [4,5-d]pyrimidine -5(H)- thiones and evaluated for antimicrobial activity and fungitoxicity.Harendra singh et. Al. 132 have synthesized 2-aryl-6-arylamino-1,2,4-thiadiazolo [3,2-b]-1,3,4-oxadiazoles and screened for fungal toxicity.Parikh et al. have synthesized variety 133 of 1,3,4-oxadiazoles bearing arylsulphonamido aryl, 134-135 mercapto, 136 quinolinyl 137 and amino moieties at 2-positionOxadiazoles…

Studies on some compounds… 40(Y) and 4’-pyridyl, benzenesulphonamidophenyl, diiodoquinolinoxy and arylsulfonamido phenyl at 5-position (X) as antimicrobial agents.H.H.Parekh and co-workers have investigated 1,3,4-oxadiazoles havingtriazine, 138-139 phenyl sulphonyl, 140 2’- isopropyl -5-methyl phenoxy methyl, 141-143dapson 144-146 moieties at position (X) and aryl, aryl amino, arylsulphonamido,substituted benzalamino moieties at 2-position (Y) and evaluated their antimicrobialactivity, General structure for above references is as under.NNXOYSO 2 NH.RX=N, SO 2 NH, ,ArylY= NH-SO 2 -R, -N=CH-R, Aryl, -NH 2 , -SH,-NHCOR,Chan, Wai Ngor and et al. 147 have synthesized 1,3,4-oxadiazole derivatives(VI) and reported as orexin receptor antagonists. Grover et al. 148 have synthesized1,3,4-oxadiazole derivatives and tested for antibacterial activity. Khan and Akhtar149have reported the anti-inflammatory activity of some new 1,3,4-oxadiazolederivatives. Ayscough and co-workers 150tested for anti-inflammatory activity.have synthesized oxadiazoles (VII) andMeNSNOFOMeMet-BUOHCONNHOHNN(VI)NO(VIIOxadiazoles…

Studies on some compounds… 41K C Ravindra, H M Vagdevi, V P Vaidya & Basavaraj Padmashali151 have prepared1,3,4- oxadiazoles linked to naptho [2,1-b] furan (VIII) and evaluated forantimicrobial and anti-inflammatory.NNO(VIII)ORVital contribution of 1,3,4-oxadiazole ring system to the medicinal chemistryas an active constituent of antibiotics made chemists to explore for its otherderivatives as therapeutic agents. Accordingly, several derivatives of 1,3,4-oxadiazoles have been designed as under.SECTION:-1.2:- SYNTHESIS AND STRUCURE ELUCIDATION OF 2 - (4 -ISOPROPOXY- PHENYL)-5 (ARYL) - 1,3,4- OXADIAZOLES.Oxadiazoles…

Studies on some compounds… 42SECTION-1.1SYNTHESIS & STRUCTURE ELUCIDATION OF 4-ISOPROPOXY- N'-[(1E)– (ARYL) METHYLENE] BENZOHYDRAZIDE.The increasing copyright literature of current years demonstrates that theazomethines derivatives are worn as superior therapeutic agents. In vision of theseconclusion, it appeared of concentration to synthesize Schiff’s bases of the belowmentioned compounds by the condensation of 4-isopropoxy benzoic acid hydrazidewith different aromatic aldehydes.CH 3H 3NH NH 2COOR-CHOgl.acetic acidEthanolCH 3Compound-(I)C H 3OOType-(I)NH NRHThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (Ia-j) have been screened for their in vitrotherapeutic assay like Antibacterial activities towards Gram positive and Gramnegative bacterial strain and Antifungal activities towards fungal strains at differentconcentrations (Minimum Inhibitory Concentration). The biological activities ofsynthesized compounds (Ia-j) have been compared with standard drugs viz.Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(Chapter-8).Oxadiazoles…

Studies on some compounds… 43Reaction SchemeCH 3C H 3OOOCH 3NH 2 NH 2 .H 2 OEthanolCH 3H 3NH NH 2COOR-CHOgl.acetic acidMethanolC H 3CH 3OR=ArylONH NHRType-(I)Oxadiazoles…

Studies on some compounds… 44IR SPECTRALSTUDIES OF 4-ISOPROPOXY BENZOICACID HYDRAZIDE.H 3 CCH 3OONH NH 2Instrument: SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2973 2975-2950 158-CH3 C-H str. (sym) 2872 2880-2860 "C-H def. (asym.) 1419 1470-1435 "C-H def.(sym.) 1384 1390-1370 "Aromatic C-H str. 3043 3090-3030 159C=C str. 1527 1540-1480 "C-H i.p. def. 1120 1125-1000 "C-H o.o.p. def. 840 835-810 "Moiety C-O-C (asym) 1101 1075-1010 160Amide -CONH- 1606 1660-1580 161Hydrazide -NH-NH 2 3395 3380-3410 "Oxadiazoles…

Studies on some compounds… 45PMR SPECTRAL STUDIES OF 4-ISOPROPOXY BENZOICACIDHYDRAZIDE.C H 3CH 3ab'OOa'bNH NH 2Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 1.33 6H doublet (CH 3 ) 2 moiety2 4.17 2H singlet(broad) -NH2(Hydrazide)3 4.59 1H multiplet -CH-(isopropyl)4 6.86-6.88 2H doublet Ar-Ha,a’5 7.72-7.74 2H doublet Ar-Hb,b’6 8.13 1H Singlet -CONH-Oxadiazoles…

Studies on some compounds… 46NH 2ONHMASS SPECTRAL STUDIES OF 4-ISOPROPOXY BENZOICACID HYDRAZIDEC H 3C H 3Om/z =194.23Oxadiazoles…

Studies on some compounds… 47MASS FRAGMENTATIONOOCOm/z = 179+NH 2 0OH C+ CH 3m/z = 179NHNH 2OO+0+0H 3CH 3OOCH 2m/z = 163NH 2H 3 CCH 3m/z = 194(M.I.P.)NHNH 2O +H 2 Cm/z = 163ONHNH 2+0m/z = 78+0HOm/z = 137ONH 2ONH 2 0m/z = 121 (B.P.)+NH +NH +C + ONHm/z = 93m/z = 104Oxadiazoles…

Studies on some compounds… 48IR SPECTRAL STUDIES OF 4-ISOPROPOXY-N'-[(1E)-(4-METHOXYPHENYL) METHYLENE] BENZOHYDRAZIDE.OOH 3 CNH NCH 3HOCH 3Instrument: SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str.(asym.) 2978 2975-2950 158-CH3 C-H str.(sym) 2833 2880-2860 "C-H def.(asym.) 1488 1470-1435 "C-H def.(sym.) 1372 1390-1370 "Aromatic C-H str. 3071 3090-3030 159C=C str. 1550 1540-1480 "C-H i.p. def. 1057 1125-1000 "C-H o.o.p. def. 842 835-810 "Moiety Ar-O-C (sym.) 1057 1075-1010 160Ether C-O-C (asym) 1287 1275-1200 158Amide -CONH- 1620 1660-1580 "Schiff -N=CH- 1596 1600-1580 "baseSec.amine -NH- 3199 3410-3380 "Oxadiazoles…

Studies on some compounds… 49PMR SPECTRAL STUDY OF 4-ISOPROPOXY-N'-[(1E)-(4-METHOXYPHENYL) METHYLENE] BENZOHYDRAZIDE.OOH 3 CNH NCH 3HOCH 3Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 1.30 6H doublet (CH 3 ) 2 moiety2 3.43 3H Singlet -N=CH-(schief.)3 3.83 1H Singlet Ar-OCH 34 4.69 1H multiplet -CH-(isopropyl)5 7.03-7.98 8H multiplet Ar-H6 8.42 1H Singlet -CONH-Oxadiazoles…

Studies on some compounds… 50MASS SPECTRAL STUDY OF 4-ISOPROPOXY-N'-[(1E)-(4-METHOXY PHENYL) METHYLENE BENZOHY DRAZIDE.OOC H 3NNHOCH 3CH 3Hm/z = 312.36Oxadiazoles…

Studies on some compounds… 51MASS FRAGMENTATIONOOH 3 CNH NCH 3m/z = 312(M.I.P.)OCH 3+0OOH 3 CNH NCH 3m/z = 297O -+HOONH Nm/z = 269OCH 3+0OH 3 CCH 3m/z = 179ONH 2+0HOONH Nm/z = 255OH+0+0HOm/z = 137ONH 2++0OH+0ONH 2m/z = 78m/z = 94m/z = 121( B.P.)Oxadiazoles…

Studies on some compounds… 52EXPERIMENTALSYNTHESIS & STRUCTURE ELUCIDATION OF 4-ISOPROPOXY- N'-[(1E)– (ARYL) METHYLENE] BENZOHYDRAZIDE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 4-ISOPROPOXY BENZOIC ACID HYDRAZIDE.A mixture of 4- isopropoxy benzoic acid ethyl ester (50gm, 0.24mol) andhydrazine hydrate (24gm, 2.0mol) was refluxed in ethanol (100ml) for 10 to 12 hrs,the completion of reaction was monitored by thin layer chromatography (TLC).aftercompletion of reaction the reaction mass was cooled at room temperature and pouredin ice water, the product was filtered and dried and finally crystallized with ethanol.Yield: 85%, m.p. - 112˚C; [C 10 H 14 N 2 O 2 ; required: C, 61.84; H, 7.27; N, 14.42 %;found: C, 61.80; H, 7.25; N, 14.39 %].[B] PREPARATION OF 4-ISOPROPOXY-N'-[(1E)-(4-METHOXY PHENYL)METHYLENE] BENZOHYDRAZIDE.A mixture of 4-methoxy benzaldehyde (4.08 gm, 0.03 mol) in ethanol (30 ml)was added to a solution of 4-isopropoxy benzoic acid hydrazide (5gm, 0.025mol)ethanol, added glacial acetic acid (2 ml) as a catalyst. The reaction mass was refluxedfor 5-6 hrs, the solvent was distilled out under reduced pressure and solid mass soobtained was isolated and purified by recrystallization from appropriate solvent , yield:90%, m.p.-185˚C; [C 18 H 20 N 2 O 3 ; found: C, 69.20, H, 6.39, N, 8.90, requires C, 69.21,H, 6.45, N, 8.97 %].Similarly, other 4-isopropoxy-N'-[(1E)-(aryl) methylene] benzohydrazide wereprepared. The physical constants are recorded in Table No. -1.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride(2:8)Oxadiazoles…

Studies on some compounds… 53[C] BIOLOGICAL EVALUATION OF 4-ISOPROPOXY-N'-[(1E)-(ARYL)METHYLENE] BENZOHYDRAZIDE.Antimicrobial testing was carried out as described in Chapter-8. The zones ofinhibition of test solutions are recorded in Graphical Chart-1a, Table-1a. Page No.-357, 358. Result and discussion is given on page No.:-359.Oxadiazoles…

Studies on some compounds… 54● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Oxadiazoles…

Studies on some compounds… 55SECTION-1.2SYNTHESIS AND STRUCURE ELUCIDATION OF 2-(4-ISOPROPOXY-PHENYL)-5 (ARYL) - 1,3,4- OXADIAZOLES.Synthesis of 1,3,4-oxadiazole derivatives has attracted considerable attentionin view of therapeutic applications. Looking to this, the synthesis of 1,3,4-oxadiazolesof type-(II) was undertaken by two different method, in which reaction of Schiff basewith Chloramine-T and KMnO 4 was taken as shown in reaction schemeOOH 3CNH NCH 3HRRoute-1- Acetone/KMnO 4Route-2- Ethanol/ Chloramine-TNNCompound-(II)Type-(II)OOH 3 CCH 3R= ArylRThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (IIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (IIa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations.(Chapter-8).Oxadiazoles…

Studies on some compounds… 56Reaction SchemeOOH 3 CNHNH 2CH 3R-CHOgl.acetic acidEthanolOOH 3 CNHNCH 3HRRoute-1Route-2EthanolChloramine-TAcetoneKMnO 4NNOOH 3 CCH 3RR= ArylType-(II)Oxadiazoles…

Studies on some compounds… 57IR SPECTRAL STUDIES OF 2-(4-ISOPROPOXYPHENYL)-5-(p-METHOXYPHENYL)-1, 3, 4-OXADIAZOLE.OH 3 COCH 3N NO CH3Instrument: SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2977 2975-2950 158-CH3 C-H str. (sym) 2830 2880-2860 "C-H def. (asym.) 1497 1470-1435 "C-H def.(sym.) 1380 1390-1370 "Aromatic C-H str. 3017 3090-3030 159C=C str. 1518 1540-1480 "C-H i.p. def. 1078 1125-1000 "C-H o.o.p. def. 819 835-810 "Moiety Ar-O-C (sym.) 1067 1075-1010 160C-O-C (asym) 1264 1275-1200 161Oxadiazole N-N str. 1040 1050-1010 "C=N str. 1609 1660-1580 "C-O-C str. 1264 1275-1200 "Oxadiazoles…

Studies on some compounds… 58PMR SPECTRAL STUDIES OF 2-(4-ISOPROPOXYPHENYL)-5-(p-METHOXYPHENYL)-1, 3, 4-OXADIAZOLE.abN NO CH 3OH 3 COa' b'CH 3c'd'cdInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz)Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 1.38 6H doublet (CH 3 ) 2 moiety2 3.88 3H Singlet Ar-OCH 33 4.65 1H multiplet -CH-(isopropyl)4 6.98-7.02 4H Double doublet Ar-Ha, a’,b,b’5 8.02-8.06 4H Double doublet Ar-Hc, c’,d,d’Oxadiazoles…

Studies on some compounds… 59MASS SPECTRAL STUDIES OF 2-(4-ISOPROPOXYPHENYL)-5- (4-METHOXY PHENYL) -1, 3, 4-OXADIAZOLENNOOH 3 COCH 3CH 3m/z = 310.34Oxadiazoles…

Studies on some compounds… 60MASS FRAGMENTATIONONNCOH 3CH 3O CH 3m/z = 310(M.I.P.)+0+0O -NONCONONm/z = 268OCH 3H 3CH 3O - +m/z = 2950+ O -0NOm/z = 237N+0O -NOm/z = 135 ( B.P.)HOm/z = 121O ++0+O+0m/z = 78m/z = 94Oxadiazoles…

Studies on some compounds… 61EXPERIMENTALSYNTHESIS AND STRUCURE ELUCIDATION OF 2-(4-ISOPROPOXY-PHENYL)-5 (ARYL) - 1,3,4- OXADIAZOLES.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 4-ISOPROPOXY BENZOIC ACID HYDRAZIDE.Pls. refer Chapter-1, Section 1.1, Page No.52[B] PREPARATION OF 4-ISOPROPOXY-N'-[(1E)-(4-METHOXY PHENYL)METHYLENE] BENZOHYDRAZIDE.Pls. refer Chapter-1, Section 1.1, Page No.52[C] PREPARATION OF 2-(4-ISOPROPOXYPHENYL)-5-(4-METHOXYPHENYL) -1, 3, 4-OXADIAZOLERoute (01):- In the solution of 4-isopropoxy-N'-[(1E)-(4-methoxy phenyl)methylene] benzohydrazide. (3.12gm, 0.01 mole) in acetone (50ml), potassiumpermanganate (3.5gm) was added then reflux for 8 hrs., the reaction mass turns frompink to brown color during the reaction. TLC was observed during the reaction (ifneeded add extra potassium permanganate) after completion of the reaction filteredthis hot solution through Buckner funnel. The product precipitated from acetone wasfiltered. Recrystallized it from proper solvent, m.p.-102◦c, yield: 70%.,[C 18 H 18 N 2 O 3;found: C, 69.62, H, 5.87, N, 9.07, requires C, 69.66, H, 5.85, N, 9.03 %].Route (02):-In the solution of 4-isopropoxy-N'-[(1E)-(4-methoxy phenyl)methylene] benzohydrazide (3.12gm, 0.01 mole) and (2 gm) of Chloramine-T wasadded. It was refluxed for 2 to 3 hrs. TLC was observed of reaction mass during thereaction, after completion of the reaction filtered the reaction mass through Bucknerfunnel while hot to remove sodium salt. Collected the product from ethanol withchilling. Recrystallized it from proper solvent.Oxadiazoles…

Studies on some compounds… 62Similarly, other 2-(4-isopropoxyphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazoles were synthesized, and their characterization data are recorded in Table-2.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)[C] BIOLOGICAL EVALUATION 2-(4-ISOPROPOXYPHENYL)-5-(ARYL) -1, 3, 4-OXADIAZOLE.Antimicrobial testing were carried out as described in Chapter-8. The zonesof inhibition of test solutions are recorded in Graphical Chart-2a. Table-2a. PageNo. - 360, 361. Result and discussion is given on page no.-362.Oxadiazoles…

Studies on some compounds… 63● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Oxadiazoles…

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Studies on some compounds… 73139. C. L. Patel and Hansa Parekh;J. Indian Chem. Soc., 65, 606-607 (1988);140. R. N. Vansdadiya, K. P. Roda and Hansa Parekh;J. Indian Chem. Soc., 65, 809-11 (1988).141. K. P. Roda, R. N. Vansdadiya and Hansa Parekh;J. Inst. Chem. 60, 157 (1988).142. R. N. Vansdadiya, K. P. Roda and Hansa Parekh;J. Indian Chem. Soc., 65, 807-09 (1988).143. R. N. Vansdadiya, K. P. Roda and Hansa Parekh;J. Indian Chem. Soc., 65, 44-45 (1988).144. M. A. Shah Safi, M. H. Meshkat Al Sadat and Hansa parekh;J. Inst. Chemists (Indian), 60, 47-48 (1988).145. M. A. Shah Safi, M. H. Meshkat Al Sadat and Hansa parekh;J. Indian Chem. Soc., 65, 64-65 (1988).146. R. N. Vansdadiya, K. P. Roda and Hansa Parekh;J. Indian Chem. Soc., 65, 782-83 (1988).147. Chan, Wai Nagor; Johns, Amand; Johnson, Chrostopher Norber; Novelli,Riccardo; Porter, and Roderi ck Alan;PCT Int. Appl. WO 2003 00 2559 A2 (2003), 81 pp; Chem. Abstr., 138,89815 (2003).148. Grover, Gaurav; Kini and Suvarana G;Indian J. of Heterocyclic Chem., 2002, 12(3), 289-290 (Eng); Chem.Abstr., 139(13), 197430h (2003).149. Khan M. S. Y. and Akhtar, M. ;Indian J. of Chemistry., 42B(4), 900-904 (Eng.) 2003; Chem. Abstr.,139(11), 164749r (2003).150. Ayscough, Andrew Paul; Davies, Stephen John; Pain, Gilles; Gillon andJean – Yves;PCT Int. Appl. WO 03 70, 711 (Cl. CO7D 271/06), 28 Aug 2003, GBAppl. 2002/4, 159, 22 Feb 2002; 85pp. (Eng); Chem.Abstr., 139(14),214470r (2003).151. Ravindra K. C., Vagdevi H. M., Vaidya V.P & Padmashali Basavaraj;Ind. J. Chem., 45B, 2506-2511, 11(2006)Oxadiazoles…

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CHAPTER - 2STUDIES ONMANNICHBASES

Studies on some compounds… 75INTRODUCTIONMannich bases containing bridged N-atom exhibit pronounced biologicalactivities. The study of mannich reaction attracted a great deal of attention to thechemists because it plays a vital role owing to their wide range of pharmacologicaland industrial applications. Mannich bases are also employed as intermediate inchemical synthesis. 1-3Mannich base derivatives with bridge N-atom have been found to be potentdrug in medicinal science and possess wide range of biological activities likeanticancer, antibacterial, antimalarial, analgesic etc. Mannich bases have gainedimportant because of their technological applications in polymer chemistry 4 ,especially as paints and surface active agents and exhibits complexation characteristicwith many transition metal ions.Mannich Reaction is one of simple strategy reported for preparing variety ofvarious organic compounds of high medicinal and biological value. Its importance inorganic synthesis is clearly evidenced from reviews of Blick, Karbe, Nobles andothers 5-10 . Besides this, the chemistry of Mannich reaction has also been reviewed in aconsiderable number of publications and patents deals with the heterocyclic systembased Mannich bases useful as chemotherapeutic agents as well as reactiveintermediates for the synthesis of various organic compounds. As a result developingnew synthetic methods for the construction of nitrogenous molecules has defined thefrontiers of organic synthesis since its very beginning 11 .Mannich reaction is a classical method for forming carbon-carbon bond inorganic synthesis. The versatility and potential to create both functional and structuraldiversity using this reaction have long stimulated the creativity of organic chemists.The increasing popularity of Mannich reaction has been fueled by the ubiquitousnature of nitrogen in drugs, natural products and biologically active compounds aswell as by its multicomponent reaction to generate diversity. As a result it hasstimulated researcher in both academic and industrial organic synthesis.Jacobson, Tollens and co-workers 12,13 was first reported the classical methodfor the aminoalkylation of acidic proton present next to carbonyl group. Then in 1917Carl Mannich was initiated the detailed study of this reaction by preparing various β-amino alkyl compounds viz. ethylenic, phenolic compounds, higher homologous ofMannichbase…

Studies on some compounds… 76ketones and heterocyclic compounds and recognized it as a general reaction foraminoalkylation 14 . In its basic form, Mannich reaction is a condensation reaction ofan aldehyde, usually formaldehyde with ammonia, a primary or secondary amine anda compound containing activated hydrogen called Substrate (R). The resultingproduct is β-amino alkylated compound having the N-atom linked to the substrate Rthrough a methylene group and is known as Mannich base. The general aspect of thisreaction is illustrated as below.-H 2 ORH + HCHO + R' 2 NH R' 2 NH CH 2 RSubstrate Amine Mannich baseA great deal of work on Mannich reaction has been reported by number ofresearch workers 15 . Until 1965, considerable work has been reported regarding thesynthesis of Mannich Bases derived from compounds containing acidic hydrogen oncarbon but only a few examples of Mannich reaction of substrates having acidicproton on a Nitrogen atom were known 16-19 .R .S. Varma and W. L. Nobles 20 . have reported Mannich bases derived fromsubstrates having active hydrogen atom on nitrogen. Tramontini Maurilio 21 reviewedmany such reactions in which Mannich bases are employed as precursors for thesynthesis of various organic compounds. From the literature survey Mannich basesrepresent a heterocyclic systems shows potential pharmaceutical activity viz.derivatives of oxadiazoles-2-thione, triazole, imidazole, thiazole, etc. 22,23 .Thus the present chapter of the thesis deals with the work based on synthesisand characterization of N-Mannich bases using Mannich reaction. Accordingly wehave prepared different compounds of N-Mannich bases by Mannich reaction ofheterocyclic moiety as secondary amine precursors with formaldehyde and tendifferent aromatic primary amines. In this chapter the brief review about the Mannichbases has been summarized in Section-2.1.Reactant, products and reaction condition in Mannich reaction:The substrate suitable for Mannich base synthesis is widely available among anumber of α-XH acidic compounds. Where X being equal to C, N or otherMannichbase…

Studies on some compounds… 77heteroatom. As a consequence a large number of substrate/amine combinations arepossible to give enormous number of Mannich bases. On the other hand the aminesemployed include ammonia as well as common aliphatic and aromatic primary orsecondary amines for the activation of formaldehyde.However very few limitations are found in the choice of amine reactants suchas for tertiary amines as it lack a proton to form intermediate amine. Among theseseveral amines, dimethyl and diethyl amine and the cyclic secondary amines likepiperidine, morpholine, piperazine are by far the most commonly used as aminocomponent in Mannich reaction. Nature of formaldehyde used in Mannich reactionmay be provided by either aqueous formaldehyde solution, trioxymethylene orparaformaldehyde 24,25 . However aqueous formalin (37-40%) is generally asatisfactory source of formaldehyde due to favorable equilibrium position andformation of stable product. Choice of solvent is often important. In the reaction,when aqueous formalin is used, the condensation reaction is commonly carried out byshaking or stirring the reactants in the absence of organic solvents or in some casesmethanol has been used as solvent.MECHANISM:In view of this conflicting evidence, Cummings and Shelton 26 investigated themechanism of Mannich reaction particularly in basic medium for which is reliablewith the result for the basic medium. They also proposed a modification inmechanism of Mannich reaction for acidic medium which was in agreement ofAlexander and Underhill.Over the years there has been much controversy about the mechanism of themannich reaction. Studies of the reaction kinetics have led to the followingmechanistic proposals.R.S.Varma and other have proposed 27 the mechanism for aminomethylation ofisatin as shown below, depending upon the order of addition of formaldehyde.According to them formaldehyde (ii) may react with dimethylamine (i) or isatin (iv)to generate aminomethylol derivative of dimethylamine (iii) or isatin (iv) to yield N-Mannich base (v).Mannichbase…

Studies on some compounds… 78C H 3C H 3NHHNO+CH 2 OOOH+C H 3H 3 C(i) (ii) (iii)(iv)(iv)HNOH 3 CO +C H 3NCH 2 O(ii)(iii)OHNOHNON-Mannich baseOHNOO(vi) CH 3NCH 3NCH 3O(v)+ H 2 ONOO+C H 3C H 3NH(vi) (i) N-Mannich base(v)NOOCH 3MECHANISM FOR THE FORMATION OF N-MANNICH BASEThe mechanism of the synthesized Mannich base with current moietyoxadiazole-2-thione is described as under.C H 3ONOHN+ HCHOOSCH 3NONSCH 2OHCH 3CH 3C H 3ONONCH 2SOH+R-NH 2OC H 3NONSCH 2 NH RCH 3CH 3N- Mannich baseMannichbase…

Studies on some compounds… 79SYNTHETIC ASPECT:Different methods have cited in literature to synthesize mannich bases byseveral Workers 28,29 using various interesting substrates.1. Seshaiah Krishnan et al. 30 have synthesized mannichbase (I) from the Schiffbases of isatin in presence of formaldehyde and diphenyl amine.RNHNR 1ORHCHOH 5 C 6H 5 C 6NHR = H, Cl, BrNR 1ONR 2(I)R 1= C 6H 5Br, C 6H 5CH 3, C 6H 5OCH 3R 2= -CH 2-(NC 6H 5) 22. Rodolfo Quevedo et al 31 have synthesized new macrocyclic compoundshaving two benzoxazine subunits joined by two ethylene bridges have beenprepared by Mannich condensation of the appropriate 4-hydroxy phenylethyl amine with an excess of formaldehyde. This is a general method forsynthesizing a new family of heterocyclophanes.(II)ORHCHORNHONH 2NRO(II)R = COOC 2 H 5 , H3. Hui Mao et al 32 have synthesized facile and diastereoselective synthesis of β-acetamido ketones and keto esters via direct Mannich-type reaction (III). AMannich type three-component reaction involving aldehydes, acetamide, andMannichbase…

Studies on some compounds… 80enolizable ketones or β-keto esters for the preparation of β-acetamido carbonylcompounds in the presence of TMSCl is described.This newly developed protocol is operationally convenient, widely applicable,and highly diastereoselective.OONHAcOCHOH 3 CCH 3CH 3R+ CH 3 CONH 2TMSClCH 3 CN, Reflux(III)O CH 3RR = Aryl aldehyde4. Rosaria Villano et al 33 have synthesized a convenient approach to α-amino-βketoestersby vinylogous Mannich reaction of masked acetoacetate. (IV) SiCl 4showed an efficient and selective catalyst for the vinylogous Mannich reactionof linear and cyclic synthetic equivalents of acetoacetate dianion, leading to α-amino-β-ketoesters in moderate to high yields and complete γ-selectivity; antidiastereoselectivewas observed by using a γ-methyl-substituted cyclicsilyloxydiene.RCHOPhNH 2 , CH 2 Cl 2CH 2 Cl 2R-CH=N-C 6 H 43 A o MS, SiO2, 1h/rt; DIPEA, SiCl 40.5h/-78 0 CC H 3NO(IV)RR=Aryl aldehydeCOOMe5. Chi and co-workers 34 have synthesized mannich base using 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, formaldehyde and phenolic derivatives inbenzene.6. Yung-son Hon et al. 35 have prepared mannich base (V) from the reaction ofphenolic compounds with a preheated mixture of dibromomethane anddiethylamine.Mannichbase…

Studies on some compounds… 81CH 3CH 3NOH[CH 2 Br 2 , NH(Et) 2 ]OH(V)7. Venkatesha Prabhu G. and Vanappayya D. 36 have synthesizedaminobenzylated mannich bases (VI) by the condensation reaction betweenheterocyclic secondary amines and benzaldehyde.CHONH 2CH 3X+NHXOHN H 2OXNCH 3NH(VI)O H C N X8. Pandeya and Sriram D. Dave 37 have synthesized mannich bases by thecondensation of the acidic group of isatin with formaldehyde and secondaryamines.9. Christos A. Kontogiorgis et al. 38 have synthesized mannich base of coumarine.10. G. Bryant and V. L. Heisey 79 in 1965 have reported the synthesis of MannichBases derived from various nitrogen containing five membered ring systemssuch as pyrole, pyrazole, benzimidazole and benzotriazole.11. A. H. El-masry and co-workers 80 have made effort to incorporate abenzimidazole into a triazole moiety by Mannich reaction of oxadiazole withdifferent secondary amines and paraformaldehyde to give Mannich basecompounds.THERAPEUTIC IMPORTANCEThe appearance of powerful and elegant Mannich reaction has stimulatedmajor advances as pharmaceutical agents of remarkable significance in medicine,Mannichbase…

Studies on some compounds… 82biology and pharmacy. It would be more worthy to discuss in brief about the historyand developments of these Mannich bases as pharmaceutical agents.Mannich bases are associated with a wide variety of biological activities andindustrial applications such as,1. Anti-inflammatory 39-412. Antifungal 423. Antitumor 434. Analgesic 445. Cytotoxic and anticancer 456. Antibacterial 467. Antipsychotic 4748, 498. Tranquilizing9. Antileishmanial 5010. Antimalarial 51B. Shivarama Holla et al. 52 have prepared mannich bases and tested them foranthelmintic activity (I) and all the newly synthesized compounds (II) were tested fortheir antibacterial and antifungal activity.NNNNNORNNSON N CH 3OO 2 NCH 3RNNSOO 2 NOCH 3(I)(II)Amodiaquine 53,54 ,a mannich base derivatives (III) which shown anantimalarial activity superior than chloroquine in areas of high chloroquine resistance.M. L. Edwards et al. 55 have prepared the mannich base of 4-phenyl-3-buten-2-one asan antiherps agent. Malcolm K. Scott and co-workers 56 have prepared the pyrrolemannich base (IV) as a potent antipsychotic agent.Mannichbase…

Studies on some compounds… 83CH 3CH 3NR 1NNR 3R 2 NN (CH 2 )nHOHONHClN(III)(IV)J. Knoll et al. 57 have prepared the mannich base (V) which was the mostpotent neuroleptic compound of a series of aryl substituted analogues. Molindone(VI) which has been reported to demostrate potent neuroleptic activity 58 . Jan Balzariniand co-workers 59 have prepared the mannich bases of chalcone showing cytotoxicactivities.H 3 CCONH 3HNNOH 3H 3CCO(V)(VI)H. S. Joshi et al. 60 have been synthesized some new amino benzylatedmannichbases and reported their antimicrobial activities.Gul H. I. et al. 61,62 have documented antifungal activity of bis mannich basesderived from acetophenones and some mono mannich bases evaluated for theiranticonvulsant activity. Shingare M. S. et al. 63 have described the synthesis and theantiviral activity of mannich bases (VII).Mannichbase…

Studies on some compounds… 84NRNSS(VII)NNHNSRR= H, 4-Me, 5-OMe, 5-Cl, 6-BrMovrin M. and Maysinger D. 64have synthesized mannich bases fromnitroxoline and reported them as biologically active agents. Ojanen T. andcoworkers 65have reported antifungal activity of some mono, bis and quaternarymannich bases derived from acetophenone. Li Y., Yang Z. S. et al.66 have synthesizedsome mannich base derivatives and reported their antimalarial activity.Lorand T. and Kocsis B. 67 have synthesized some new mannich ketones andreported their antibacterial activity. Erol D. D., Rosen A. et al. 68 have synthesizedsome novel mannich base derivatives from 6-acyl-3-(3,5-dimethylpiperidinomethyl)-2(3H)-benzoxazolones and reported their biological activities. H. M. Hassan 69 havesynthesized some new mannich bases containing 1,8-napthyridine moiety andreported their antimicrobial activity.K. C. Ravindra, H. M. Vagdevi and coworkers 70 have documentedantimicrobial and anti-inflammatory activity of N-mannichbases (VIII) derived from5-Naphtho [2,1-b]furan -2-yl-1,3,4-oxadiazole-2-(3H)-thione with different aromaticamines in presence of formaldehyde.NHRNNO(VIII)OSOzair Alam, Mohd. Imran and S.A.Khan 71 have synthesized annich base(IX) from some substituted 2-amino pyrimidine with morpholine in presence offormaldehyde and evaluated their antimicrobial and anticonvulsant activities.Mannichbase…

Studies on some compounds… 85R 1R 2R 3N NH NON(IX)Ashok kumar and co-workers 72 have synthesized Mannichbase (X) of someanthranilic acid derivatives in presence of formaldehyde and different aromaticamines and evaluated for their anti-inflammatory activity.R 1XCOOHNHNHRNOR= Aromatic aldehydesR 1 = Aromatic amines(X)Hassan A. Albar, and co-workers 73 have synthesized Mannichbases (XI) fromsome unsaturated 1,3-diketoesters derivatives and studied their biological activity.NHSO 2 NHRSNN N SNOX(XI)Mannichbase…

Studies on some compounds… 86Senshaiah Krishnan Sridhar and Atmakuru Ramesh 74 have synthesized a seriesof N- Mannich bases of isatin derivatives (XII)..The synthesized compounds weretested for their analgesic, anti-inflammatory and antipyretic activity.RNR 1O(XII)NNPhPhWhere, R= H, Cl, Br,R 1 = Aromatic amnesDharmarajan Sriram and co-workers 75have synthesized a series ofaminopyrimidinimino isatin derivatives. These synthesized N-Mannich bases (XIII)were evaluated for non nucleoside HIV-1 reverse transcriptase inhibitors and alsoshowed antibacterial activity.NOMeNCH 2OMeONOMeNC H 2R(XIII)Where, R=HNEtEtHNN CH 3HNN Ph HN O, ,,M. Senthilraja and S. A. Thangadhurai 76 have synthesized N-Mannich basesby the reaction of Schiff bases of isatin with pyrimethamine (XIV). These synthesizedN-Mannich bases were screened for antibacterial and antifungal activity.Mannichbase…

Studies on some compounds… 87NNH 2NClNNOC 2 H 5C H 2RWhere, R=Secondary amine(XIV)V. K. Saxena and Rita Nigam 77 have synthesized N-Mannich bases by thereaction of Schiffbases of isatin with 2-amino-4-phenyl-5-(4-substituted/unsubstituted-phenoxyphenylazo)-thiaxoles. These synthesized N-Mannich bases screen forcardiovascular, anti-inflammatory and antiviral activity (XV).H 5C 6NRONNSNO(XV)Where, R = H, Cl.R 1= Secondary amineNH 2C R 1T. K. Dave and V. A. co-workers 78 have synthesized a of series 4-amino-3-mercapto-5-pyridin-3´-yl-[1,2,4]-triazole which exhibit antimicrobial and antitubercular activity.In view of the importance of mannich bases as versatile syntheticintermediates and the availability of scanty literature on therapeutic properties, wehave undertaken the preparation of mannich bases in following section.SECTION-2.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-(4-ISOPROPOXY PHENYL) 3-N-[(ARYL) AMINO METHYL]-1,3, 4 OXADIAZOLE -5 (4H) –THIONE.Mannichbase…

Studies on some compounds… 88SECTION-2.1SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-(4-ISOPROPOXYPHENYL) 3-N-[(ARYL) AMINO METHYL]-1, 3, 4 OXADIAZOLE -5 (4H) –THIONE.In view of getting better therapeutic agent and considering the association ofvarious biological activity with 2-(4-isoprpoxyphenyl)-1,3,4-oxadiazole-5(4H)-thionenuclei, the preparation of mannich bases of Type (III) have been undertaken from 2-(4-isoprpoxyphenyl)-1,3,4-oxadiazole-5(4H)-thione with primary amines andformaldehyde in methanol.ONOH 3CCH 3NHSHCHOR-NH 2RNHCompound- (III)(Type-III)ONOH 3CCH 3NSR= Aromatic aminesThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (IIIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive and Gramnegative bacterial strain and Antifungal activities towards fungal strains at differentconcentrations (Minimum Inhibitory Concentration). The biological activities ofsynthesized compounds (IIIa-j) have been compared with standard drugs viz.Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations,(Chapter-8).Mannichbase…

Studies on some compounds… 89Reaction schemeCH 3H 3COONH NH 2CS 2/KOHEthanolCH 3HH3CN NOOSHCHOSec.amineRNHCH 3H 3CN NOOSType- (III)R = Aromatic aminesMannichbase…

Studies on some compounds… 90IR SPECTRAL STUDIES OF 2-(4-ISOPROPOXYPHENYL)-3-[(4-METHOXYPHENYL) AMINO METHYL] - 1, 3, 4-OXADIAZOLE-5(4H) –THIONE.NHOCH 3ONOH 3CCH 3NSInstrument: SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str.(asym.) 2964 2975-2950 81-CH3 C-H str.(sym) 2830 2880-2860 "C-H def.(asym.) 1490 1470-1435 "C-H def.(sym.) 1341 1390-1370 "Aromatic C-H str. 2996 3090-3030 82C=C str. 1545 1540-1480 "C-H i.p. def. 1088 1125-1000 "C-H o.o.p. def. 841 835-810 "CH 2 str 1447 1500-1350 "Moiety Ar-O-C (sym.) 1238 1275-1200 83Oxadiazole C-O-C str 1088 1075-1010 84Thione C=S 1191 1200-1050 "C-N str 1212 1220-1020 "Ether C-O-C str 1238 1275-1200 "Sec.amine -NH- 3122 3410-3380 "Mannichbase…

Studies on some compounds… 91PMR SPECTRAL STUDIES OF 2-(4-ISOPROPOXYPHENYL)-3-[(4-METHOXYPHENYL) AMINO METHYL] - 1, 3, 4-OXADIAZOLE-5(4H) –THIONE.Oa bH 3 COCH 3a'b'N NScNHdH 3 COd'c'Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signal Signal position Relative No. Multiplicity Inferenceno. (δppm) of protons1 1.38 6H doublet (CH 3 ) 2 moiety2 2.22 1H Singlet -CH 2-3 3.44 3H Singlet Ar-OCH 34 4.68 1H multiplet -CH- (isopropyl)5 5.98 1H Singlet -NH (mannich.)6 6.98-7.02 4H multiplet Ar-Ha,a’,b,b’7 7.68 2H doublet Ar-Hc, c’8 7.83 2H doublet Ar-Hd, d’Mannichbase…

Studies on some compounds… 92MASS SPECTRAL STUDIES OF 2-(4-ISOPROPOXYPHENYL)-3-[(4-METHOXYPHENYL) AMINO METHYL] - 1, 3, 4-OXADIAZOLE-5(4H) –THIONE.NHOOH 3 CCH 3NNSm/z = 371.45OCH 3Mannichbase…

Studies on some compounds… 93MASS FRAGMENTATION+0CH 3H 3 COSm/z = 236+N NH0OH 3 CO+0N N NHOSm/z = 283N NOH 3 COSCH 3NHCH 3N NOH 3 COSm/z = 372(M.I.P.)+OH0NH+0N N NHOH 2 CO Sm/z = 326m/z = 357CH 3O+0CO+N 0O+H 3CH 3Nm/z = 177+O -OO+0m/z = 78m/z = 135( B.P.)m/z = 94Mannichbase…

Studies on some compounds… 94EXPERIMENTALSYNTHESIS& STRUCTURE ELUCIDATION OF 2-(4-ISOPROPOXYPHENYL)-3-N-(ARYL) AMINO METHYL -1, 3, 4 OXADIAZOLE -5 (4H) –THIONE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 4-ISOPROPOXY BENZOIC ACID HYDRAZIDE.Pls. refer Chapter:-1, Section:-1.1, Page no. : - 52[B] PREPARATION OF 2-(4-ISOPRPOXYPHENYL) - 1,3,4 – OXADIAZOLE-5(4H)-THIONE.To a cold stirred solution of 4-isopropoxy benzoic acid hydrazide(4 gm, 0.02mole) in ethanol (50ml) containing potassium hydroxide (1.5 gm, 0.02 mole), carbondisulfide (8 gm, 0.1 mole) was added gradually. The reaction mixture was heatedunder reflux on a steam-bath until hydrogen sulfide evolution ceased. Ethanol wasrecovered by distillation under reduced pressure and the residue was stirred withchilled water, filtered and the filtrate was neutralized with dilute hydrochloric acid.The product was filtered, washed with water & recrystallized from methanol. Yield:82%, m.p.167 ◦ c., [C 11 H 12 N 2 O 2 S; found: C, 55.85, H, 5.15, N, 11.80, requires C,55.91, H, 5.12, N, 11.86 %].TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)[C] PREPARATION OF 2-(4-ISOPROPOXYPHENYL)-3-N-[(4-METHOXYPHENYL) AMINO METHYL] - 1, 3, 4-OXADIAZOLE-5(4H) -THIONE.A solution of the 4-methoxy aniline (1.5 gm, 0.01 mole) in the methanol(10ml) was added drop wise to a cold stirred solution of 2-(4-isoprpoxyphenyl) - 1,3,4– oxadiazole -5(4H)-thione (2.5 gm, 0.01 mole) in methanol (10ml) containingformaldehyde (4 ml) and the reaction mixture stirred for 24 hrs at room temperature.Mannichbase…

Studies on some compounds… 95The precipitated product was filtered, washed with cold methanol, dried it andrecrystallized it from DMF-ethanol solvent mixture to get pure product. Yield: 75%,m.p.154 ◦ c., [C 19 H 21 N 3 O 3 S; found: C, 61.49, H, 5.78, N, 11.34, requires C, 61.44, H,5.70, N, 11.31 %].Similarly, other 2-(4-isopropoxyphenyl)-3-N-[(aryl)aminomethyl]-1,3,4-oxadiazole -5(4H)-thione were prepared. The physical constants are recorded inTable No. -3.[D] BIOLOGICAL EVALUATION OF 2-(4-ISOPROPOXYPHENYL)-3-N-[(ARYL) AMINO METHYL] - 1, 3, 4-OXADIAZOLE- 5(4H) –THIONE.Antimicrobial testing were carried out as described in Chapter-8. The zonesof inhibition of test solutions are recorded in Graphical chart -3a, Table-3a. PageNo. - 363, 364. Result and discussion is given on page no.:- 365.Mannichbase…

Studies on some compounds… 96● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Mannichbase…

Studies on some compounds… 97REFERENCES: (Chapter -1: Ref. No.:- 1-84)1. R. Caganiat, G. Kirsch, M. Wierzbicki, K. Lepage et al.;Eur. J. Med. Chem., 15, 439 (1980).2. J. R. Dimmock, S. K. Raghavan, B. M. Logan and G.E. Begam;J. Med. Chem., 18, 249 (1983).3. Maurilio Tramontini and Luigi Angiolini;Chemistry and uses (CRC Press, Ann Aror,-Londan) (1994).4. M. Traimontini, L. Angolini and N. Ghedini;Polymer, 29, 271 (1988).5. F. F. Blick; “Organic Reactions”Vol-I, John Wiley and Sons. New York, pp.303-341.6. H. Karbe;Arch. Pharm., 283, 38 (1950).7. L. Nobles;Pharm. Sci. 4 th Ann., Coll. Pharm., Uni. Texas, Austin, pp.149-185 (1961).8. B. Reichert;Pharm. Ind., 9, 375 (1952).9. K. W. Rosenmund;Pharm. Ztg-nachr., 88, 856 (1952).10. K.W. Merz;Pharmazine, 11, 505 (1956).11. F. Wolher;Ann. Phys. Chem. 12, 253 (1828).12. Jacobson;J. Am. Chem. Soc., 67, 1999 (1945).13. Tollens, Van and Marle;Ber., 36, 1351 (1903).14. Mannich and Krosche;Arch. Pharm., 250, 647 (1912).15. J. R. Feldman and E.C. Wagner;J. Org. chem., 7, 31 (1942).16. H. Hellmann and I. Loschmann;Mannichbase…

Studies on some compounds… 98Chem. Ber, 87, 1684 (1954).17. M. B. Moore and R.T. Rapela;J. Am. Chem. Soc., 68, 1657 (1946).18. R. O. Atkinson;J. Chem. Soc., 1329 (1954).19. R. Huttel and P. Jochum;Chem. Ber., 85, 820 (1952).20. R. S. Varma and W. L. Nobles;J. Hetrocyclic Chem., 3, 462 (1966).21. Tramontini Maurilio;Synthesis, 775 (1973).22. R. S. Varma and W. L. Nobles;J. Med. Chem., 10, 972 (1967).23. R. S. Varma and W. L. Nobles;J. Med. Chem., 10, 972 (1967).24. S. B. Britton, H. C. Caldwell and W. L. Nobles;Pharm. Assoc. Sci. Ed., 43, 644 (1954).25. J. F. Walker and Chaduli;A. F. Ind., Eng., 9, 974 (1947).26. Cummings and Shelton;J. Am. Chem. Soc., 25, 419 (1960).27. R. S. Varma;J. Ind. Chem. Soc., 81, 635 (2004).28. Mannich and kathuer;Arch. Pharm., 18, 257 (1919).29. Sabastiyan A. and Venkappyya D.;J. Indian chem. Soc., 61, 16 (1984).30. Seshaiah Krishnan, Sridhar et al.;Biol. Pharm. Bull, 24(10), 1149-1152 (2001).31. R. Quevedo, B. Moreno-Murillo, Tetrahedron Letters. 50 , 936–938, (2009)32. H. Mao, J. Wan, Y. Pan; Tetrahedron,65, 1026–1032.(2009)Mannichbase…

Studies on some compounds… 9933. R. Villano, M. R. Acocella, Antonio Massa, Laura Palombi and Arrigo ScettriTetrahedron,63, 12317–12323, (2007).34. Chi K.-W., Wei H. C., Kottke T., Lagow R. J.;J. Org. Chem., 61, 5684 (1996).35. Yung-Son Hon, Yu-Yu Chou and I-Che Wu;Synthetic Comunication, 34(12),2253-2267 (2004).36. Venkatesha Prabhu G. and Vanappayya D.;J.Indian Chem.Soc., 72,511-514,681-684 (1995).37. Pandeya S. N., Sriram D.;Acta Pharm. Turc., 40(1), 33-38(Eng.) (1998),Chem.Abstr., 129, 109060c, (1998).38. Christos A. Kontogiorgis and Dimitra J. Hadjipavlou-Litina;J. Med. Chem., 48, 6400-6408 (2005).39. Hadjipavlou Litina D., Geronikaki A., Sotiropoulou E.;Res. Commun. Chem. Pathol. Pharm., 790, 355-362 (1993).40. Gavalas A., Hadjipetrou L., Kourounakis P.;J. Pharm. Pharmacol., 50, 583-591 (1998).41. Satyanarayana D., Gorge S., Subrahmanyam E. V., Kalluraya B.;Boll. Chim. Farm., 140, 228-232 (2001).42. Pattanaik J. M., Pattanaik M., Bhatta D.;Indian J. Heterocycl. Chem., 8(1), 75-76(1998); Chem.Abstr., 130,66444g(1999).43. Piao Riyang, Liu Baili, J. Zhizhong et al.;Zhongguo Yaowu Huaxue Zazhi Bianjibu, 8(3), 157-162(ch) (1998).44. R. H. K. Foster and A. J. Carman;J. Pharmacol. Exp. Ther., 91, 195 (1947).45. Dimmock J. R.and Kumar P.;Curr. Med. Chem., 4, 1-22 (1997).46. J. N.Gadre, C. S. Thatte and Pramod Vele;Indian J. heterocyclic Chem., 8, 71-74 (1998).47. Rae Ducan Robertson and Gibson Samuel George;Mannichbase…

Studies on some compounds… 100PCT Int. Appl. Wo, 98, 21, 206, EP Appl.96/203,175 (1996);Chem.Abstr.,129,27899u (1998).48. J. Knoll;Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 236, 92 (1959).49. J. Knoll;Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 238, 114 (1960).50. V. J. Ram and N. Haque;Indian J. Chem., 34, 514 (1995).51. L. H. Schmidt and Ruth Crosby;Antimicrobial agents and Chemotherapy, 15(5), 672-679 (1978).52. B. Shivarama Holla, B. Veerendra, M. K. Shivananda, K. P. Latha, V. P.Vaidya;Indian J. Heterocycl. Chem., 13(1), 61-64 (2003).53. Nevill C. G., Verhoeff F. H., Munafu C. G., VanderKaay H. J.;E. AFR. Med. J., 71, 167-170 (1994).54. Panali L. K., Assicoulibaly L., Kaptue B., Konan D., Ehouman A.;Bull. Soc. Path. Exo., 87, 244-247 (1994).55. M. L. Edwards, H. W. Ritter, D. M. Stemerick and K. T. Stewart;J. Med. Chem., 26, 431-436 (1983).56. Malcolm K. Scoott, Gregory E. Martin, Deena L. DiStefano and J. L.Vaught;J. Med. Chem., 35, 552-558 (1992).57. J. Knoll, K. Nador, B. Knoll, J. Heidt and J. G. Nievel;Arch. Int. Pharmacodyn. Ther., 130, 155 (1961).58. D. M. Gallant and M. P. Bishop;Curr. Ther. Res., Clin. Exp., 10, 441 (1968).59. Jonathan R. Dimmock, N. Murthi Kandepu, Erik De Clercq and JanBalzarini;J. Med. Chem., 41, 1014-1026 (1998).60. H. S. Joshi;J. Ind. Chem. Soc., 80, 711-713 (2003).61. Gul H.I.,Ojanen T. et al.;Mannichbase…

Studies on some compounds… 101Biol. Pharm. Bull. , 25(10), 1307-10 (2002).62. Gul H. I., Calis U. et al.;Bioorg Med.Chem., 11(20), 4363-8 ( 2003).63. Shingare M. S., Mane D.V., Shinde D. B., Thore S. N.;Asian J.Chem., 8(2), 225-8 (1996).64. Movrin M., Maysinger D. et al.;Pharmazie, 35(8), 458-60 (1998).65. Gul H. I., Ojanen T. et al.;Arzneimittelforschung, 51(1),72-5 ( 2001).66. Li Y., Yang Z. S., et al.;Bioorg. Med. Chem.,11(20), 4363-8 (2003).67. Lorand T., Kocsis B. et al.;Eur. J. Med. Chem., 37(10), 803-12 (2002).68. Erol D. D., Rosen A. et al.;Arzneimittelforschung, 39(8), 851-3 (1989).69. H. M. Hassan, S. A. M. Shedid;J. Serb.Chem. Soc., 63(2), 125-130 (1996).70. K. C.Ravindra, H. M. Vagdevi, V. P. Pandya;Indian J. Chem., 45 (B), 2506-2511 (2006).71. Ozair Alam, Mohd. Imran and S.A.Khan;Indian J. Heterocycl. Chem., 14(4), 293-296 (2005).72. Preeti Rani, V. K. Shrivastav and Ashok kumar;Indian J. Chem., 34(B), 23-29 (1996).73. Hassan A. Albar, Mohamad S I Makki and Hassan M Faiallah;Indian J. Chem., 42(B), 1729-1733 (2003).74. Senshaiah Krishnan Sridhar and Atmakuru Ramesh;Biol. Pharm. Bull., 24 (10), 1149-1152 (2001).75. Dharmarajan Sriram, Tanushree Ratan Bal and Perumal Yogeeswari;J. Pharm Pharmaceult Sci., 8 (3), 565-577 (2005).76. M. Senthilraja and S. A. ThangadhuraiInt. J. Chem. Sci., 2 (3), 433 (2004).77. V. K. Saxena and Rita Nigam;Mannichbase…

Studies on some compounds… 102J. Ind. Chem. Soc., 68, 307-308 (1991).78. T. K. Dave, D. H. Purohit, J. K. Akbari and H. S. Joshi;Indian J. Chem., 46B, 352-356 (2007).79. G. Bryant and V. L. Heisey;J. Am. Chem. Soc., 68, 2486 (1946).80. A. H. El-masry, H. H. Fahmy and S. H. Ali Abdelwahed;Molecules, 5, 1429 (2000).81. V. M. Parikh; “Absorption spectroscopy of organic molecule” Additionweslay Pub. Co. London, 243, 258 (1978).82. A. R. Kartizky and R. Alan Jones;J. Chem. Soc., 294z (1960).83 F.V.Loffe;Khim. Geterokeiki Sodein, 6, 1089 (1968); Chem. Abstr., 70, 72338 (1986).84. D.L.Paria, G. M. Lampman and G. S. Kriz;Introduction to spectroscopy college publishing, Philadelphia, p-46 (1979).Mannichbase…

CHAPTER - 3STUDIES ONPYRAZOLINES

Studies on some compounds… 103INTRODUCTIONThe growing potent literatures of recent years demonstrate that Chalconebeing a very active intermediate through which novel heterocycles with promisingbiological profile can be designed. The term Chalcone was first coined by Kotaneckiand Tambor 1 who did pioneering work in the synthesis of natural coloringcompounds. They are characterized by their possession of C 6 (A)-CO-CH=CH-C 6 (B),structure in which two aromatic rings A and B, are linked by an aliphatic three carbonchain.1O3A2(I)BChalcones are phenyl styryl ketones containing reactive keto-ethylinic group(-CO-CH=CH-). Chalcones are also known as benzalacetophenones or benzylideneacetophenones the alternative name given to chalcones are β-phenyl acrylphenone γ-oxo-α , γ-diphenyl- α -propylene , α -phenyl- β -benzoethylene, 1,3-disubstituted-2-propen-1-ones,SYNTHETIC ASPECTA considerable variety of methods are available in literature for the synthesisof chalcones. The most convenient method is the one that involves the Claisen-Schmidt condensation of equimolar quantities of aryl methyl ketones with arylaldehyde in presence of alcoholic alkali. 2R C HO+ R 1 C CH 3OalkaliRCHCHCR 1OPyrazolines…

Studies on some compounds… 104Several condensing agents are used such as alkali of different strength 3,4anhydrous aluminium chloride, 5 boron trifluoride, 6 aqueous solution of borax, 7 aminoacids, 8 phosphorousoxychloride, 9 piperidine, 10 hydrochloric acid, 11-12 perchloricacid 13 , etc. Different methods of synthesis of 1,3-disubstituted-2-propen-1-ones can bequoted as below.1. By Fridel Craft cinnamoylation. 142. By Nencki reaction with cinnamic acid on aromatic compounds. 153. By Fries rearrangement of aryl cinnamates. 16174. By diazo coupling of phenyl diazonium chloride with benzoyl acrylic acid.Formation of 1,3-disubstituted-2-propen-1-ones proceeds through Claisen-Schmidt type condensation and the process is catalyzed by the presence of alkali. 18Following depicted steps are involved in the reaction mechanism.MECHANISM1.CH 3COR + OH- - CH 2COR+ H 2 O2.R'COR' C + O -HH3.R' C + O -+ - CH 2CORR' CO -CH 2CRHHOO -OH4.R'CCH 2CR +H 2 OR' CCH 2CR+ HO-HOHOOH5.R'CCH 2CRR' CH CH CR+ H 2 OHOOThe intermediate aldol type products formed readily undergoes dehydrationeven under mild condition, particularly when R and R’ are aryl groups.Pyrazolines…

Studies on some compounds… 105REACTIVITY OF CHALCONESThe chalcones have been found to be useful for the synthesis of variety ofheterocyclic compounds is as under.(a)Pyrazolines 19 and their derivatives can be prepared by the condensation ofchalcones with hydrazine hydrate and acetic acid.(b) Chalcones on reaction with semicarbazide hydrochloride in ethanol affords 1-(c)(d)(e)(f)carboxamide pyrazolines. 20Chalcones on condensation with malononitrile and ammonium acetate yields2-amino-3-cyanopyridines. 21Chalcones on reaction with 2-aminopyridine in glacial acetic acid affordspyrido pyrimidines. 22Isoxazoles 23 can be prepared by the reaction of chalcones with hydroxylaminehydrochloride and sodium acetate.Chalcones on treatment with urea in presence of alkali affords 2-oxopyrimidines. 24(g) Chalcones on reaction with thiourea in presence of alkali/acid yields 2-(h)(i)(j)(k)(l)(m)(n)thiopyrimidines. 25Chalcones on treatment with guanidine hydrochloride in presence of alkaliaffords 2-aminopyrimidines. 26Cyanopyridone 27 derivatives can be prepared by the condensation of chalconeswith ethyl cyanoacetate.Chalcones react with monoethanolamine in ethanol gives 1,4-oxazipines.28Oxirane 29 can be prepared by the reaction of Chalcone with H 2 O 2 in basicmedia.Chalcones on reaction with barbituric acid gave barbitone 30 derivatives.Chalcone gives imine derivatives with amine in presence of sulfuric acid ascatalyst. 31Chalcones on condensation with malononitrile in pyridine forms 2-amino-3-cyanopyrans. 32(o) Chalcones react with P 2 S 5 yielded 2-isothiazolidines. 33(p)Chalcones react with sodium nitrile in presence of glacial acetic acid inethanol produces 2-1H-pyrimidines. 34(q) Chalcones with 2-amino thiophenol in acetic acid produces 1,5-thiazepines. 35Pyrazolines…

Studies on some compounds… 106THERAPEUTIC IMPORTANCE1,3-Disubstituted-2-propen-1-ones and its derivatives are widely used inpharmaceutical field. Considerable interest has been shown in the chemistry of 1,3-disubstituted-2-propen-1-ones due to their wide spectrum of therapeutic activitieswhich are listed as under.1. Antiallergic 362. Antiinflammatory 37-383. Antiviral 394. Anti HIV 405. Carboxygenase inhibitor 416. Antitumor 42-437. Antimalarial 448. Anticancer 459. Antileishmanial 4610. Insecticidal 47-4811. Antiulcer 4912. Bactericidal 50-5113. Fungicidal 52-5314. Anthelmintics 54Aldose reductase inhibitor activity of Chalcone derivatives have been reportedby Okuyama et al. 55 They are also associated with antitumor and antifungal activity asreported by A. Tsotitns and coworkers. 56 Antifeedant activity of chalcones have beenobserved by Sharma and Sreenivasulu. 57Ezico et al. 58have demonstrated that Chalcone possess a valuableantiproliferation activity both on sensitive cancerous cell and on cell which areresistant to common chemotherapeutic drugs. Some of the chalcones have beenpatented for their use in treatment of glucoma 59 and showed antifungal,l 60-61 aldosereductase inhibitors, 62anticancer 63 and antimicrobial 64-65 activities.N. Liming et. al., 66 have synthesized 1,3-disubstituted-2-propen-1-ones and67screened for their anti-inflammatory and cardiovascular activity. K. Srinivas et. al.,have synthesized 1,3-disubstituted-2-propen-1-ones as a antitumor agent. Ko Horng-Huey et. al., 68 have reported 1,3-disubstituted-2-propene- 1-ones as anti-inflammatoryagent. N. Kazuhiko et. al., 69 have synthesized 1,3- disubstituted-2-propen-1-ones asPyrazolines…

Studies on some compounds… 107carcinogen inhibitors. Antitubercular activity of 1,3-disubstituted-2-propen-1-onesderivatives have been reported by L. Yuh- Meei et. al., 70 B. P. Das et. al., 71 havefound that 1,3-disubstituted-2-propen- 1-ones possesses larvicidal properties. K. Min-Young et. al., 72 have synthesized 1,3-disubstituted-2-propen-1-ones and tested fortheir matrix metallo proteinase inhibitor activity.L. Mei et. al., 73 have prepared antimalarial 1,3-disubstituted-2-propen- 1-ones.O. Veronika et. al., 74 have synthesized 1,3-disubstituted-2-propen-1- ones andscreened as cardiovascular agents. Moreover, it has been found that 1,3-disubstituted-2-propen-1-ones possess nitric oxide inhibitor, 75-76 anti-HIV 77-78 and antiproliferative79-80activities. H. H. Ko et. al., 81 have prepared some new 1,3-disubstituted-2-propen-1-ones for potent inhibition of platelet aggregation. Z. H. L. et. al., 82 have reportedsome 1,3-disubstituted- 2-propen-1-ones as antiparasitic. G. M. L. et. al., 83 havedocumented the synthesis and biological activities of 1,3-disubstituted-2-propen-1-ones as antiplasmodial. C. X. Xue et. al., 84 have documented 1,3-disubstituted-2-propen-1-ones as antimalarial agents.M. Satyanarayana et. al., 85 have synthesized 1,3-disubstituted-2- propen-1-ones as antihyperglycemic agents (II). O. Sahzevari et al. 86 have synthesized 1,3-disubstituted-2-propen-1-ones as anticancer agent, which are particularly cytotoxictowards K562 leukemia cells. Furthermore, M. J. Alcaraz et. al., 87 have described therole of nuclear factor kappa-β and hemeoxygenase-1 in the action of an antiinflammatory1,3-disubstituted-2-propen-1-ones in RAW 264.7 cells.OH 3CH 3 OHCNOR(II)R=substituted phenylO. Nerya et. al., 88 have prepared some new 1,3-disubstituted- 2-propen-1-onesas potent tyrosinase inhibitors. O. Sabzevari et. al., 89 have reported some new 1,3-disubstituted-2-propen-1-ones as Molecular cytotoxic mechanisms of anticancerhydroxy chalcones (III). F. Hollosy et. al., 90 have prepared some new 1,3-disubstituted-2-propen-1-ones as Plant-derived protein tyrosine kinase inhibitors.Pyrazolines…

Studies on some compounds… 108OMeOOOMeOH(III)Recently, H. S. Ban et. al., 91 have reported some newer 1,3-disubstituted- 2-propen-1-ones as inhibition of lipo poly saccharide-induced expression of induciblenitric oxide synthase and tumor necrosis factor-α by 2'-hydroxy chalcone derivativesin RAW 264.7 cells. S. Feldbaek Nielsen et. al., 92 have synthesized some 1,3-disubstituted-2-propen-1-ones derivatives (IV) as antibacterial agent.NNNHNROR=substituted phenyl(IV)P. P. Yadav et. al., 93 have synthesized nitrogen and sulfur containing furanoflavonoids and thiophenyl flavonoids (V), which have been screened for antimicrobialactivity.OXOHR(V)X= NCH 3/SR=H/OCH 3J. N. Dominguez et. al., 94 have synthesized 1,3-disubstituted-2-propen- 1-onesand reported their activity as antimalarial agents.W. Duck Seo et. al., 95 have synthesized 1,3-disubstituted-2-propen-1- ones(VI) and reported as α-glucosidase inhibitors.Pyrazolines…

Studies on some compounds… 109OOC H 3SNHROR=substituted phenyl(VI)(VI)M. Larsen and et. al., 96 have synthesized 1,3-disubstituted-2-propen-1- ones(VII) and reported their antiplasmodial activity.R(VII)OR=substituted phenylRMoreover, S. Khatib et. al., 97 have reported some novel 1,3- disubstituted-2-propen-1-ones as potent tyrosinase inhibitors (VIII). Seo et. al., 98 reported the 1,3-disubstituted-2-propen-1-ones as α-glucosidase inhibitors.OHHOOHOHO(VIII)A. Araico et. al., 99 have synthesized 1,3-disubstituted-2-propen-1-ones asinhibitor of cyclo-oxygenase-2 and 5-lipoxygenase.S. H. L. et. al., 100 have designed and synthesized some new 1,3- disubstituted-2-propen-1-ones and reported their anti-inflammatory activity.Pyrazolines…

Studies on some compounds… 110P. Boeck et. al., 101 have synthesized some newer 1,3-disubstituted-2- propen-1-ones (IX) with antileishmanial activity, in which analogues contain nitro, fluorineor bromine group respectively displayed increased selectivity against the parasites ascompared with natural 1,3-disubstituted-2-propen-1- ones. X. Wu et. al., 102 havesynthesized ferrrocenyl 1,3-disubstituted-2-propen-1-ones and reported theirantiplasmodial activity.OHOR 3 R 1R 1=NO 2, R 2= H, R 3=HMeOOMeR 2(IX)R 1=H, R 2=F, R 3=HR 1=NO 2, R 2=H, R 3=BrR. R. Kamble et. al., 103 have reported novel 1,3-disubstituted-2- propen-1-ones(X) having potent biological activity.OHORHCHCC(X)NH ONR=SUBSTITUTED PHENYLM. S. Yar et. al., 104 have synthesized some 1,3-disubstituted-2-propen- 1-ones(XI) having antimicobacterial activity.CH 3ROH(XI)OR=substituted phenylPyrazolines…

Studies on some compounds… 111F. Jin et. al., 105 have reported structural requirements of synthetic derivative ofbutene, a natural 1,3-disubstituted-2-propen-1-ones (XII) for anti-inflammatoryactivity.OMOM OMOMOOMOM(XII)These valid observations about the therapeutic applications of 1,3-disubstituted-2-propen-1-ones led us to explore chemistry and biological activities of1,3-disubstituted-2-propen-1-ones by synthesizing their several derivatives viz.,pyrazolines, N-substituted pyrazolines, which can be summarized in the followingsections.SECTION-3.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3 -DICHLORO N-(3-SUBSTITUTED STYRYL CARBONYL)BENZAMIDE.Pyrazolines…

Studies on some compounds… 112INTRODUCTIONPyrazoles are well known five membered heterocyclic compounds and severalprocedures for its synthesis have been extensively studied. Such studies have beenstimulated by various promising applications, especially in the case of N-substitutedpyrazole derivatives. In fact, certain N-substituted pyrazoles are used as analgesic,anti-inflammatory, antipyretic, agrochemicals whereas some others are being studiedfor their medicinal interest.The knowledge of such applications has pointed out that N-substitutedpyrazoles are important target to be prepared to our interest on synthesis andmolecular structure determination of some types of pyrazoles.The pyrazole ring system (I) consists of a doubly unsaturated five memberedring containing two adjacent nitrogen atoms. Knorr 106 first synthesized a compoundcontaining this system in 1883 by a reaction of ethylacetoacetate with phenylhydrazine which yield 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (II).NNHONPhNCH 3R 2 R 3NR 1 N(I) (II) (III)RThe discovery of pyrazole derivatives as antipyretic agents dates back to 1884,when the German chemist Ludwig Knorr 107 attempted to synthesize quinolinederivatives with antipyretic activity and accidentally obtained antipyrine (2,3-Dimethyl-1-phenyl-3-pyrazolin-5-one), which has analgesic, antipyretic andantirheumatic activity. Aminopyrine, a more potent analogue was synthesized thereafter and these drugs were widely used in market as antipyretics. In pyrazole ring ifone carbonyl group comes at 5 position it is known as pyrazolone. The pyrazoloneexists as a mixture of the three most probable tautomeric structures. Pyrazolone hasbeen extensively explored for its importance in the field of pharmaceuticaldevelopment. This five member heterocyclic ring has attracted attention word wide.Pyrazolines…

Studies on some compounds… 113Pyrazoles and their reduced forms pyrazolines are well known nitrogencontaining five membered heterocyclic compounds (III) which possess widespreadchemical and pharmacological applications 108-110 such as analgesic, antipyretic andantirheumatic. 111-112 These derivatives are also well known for their pronounced antiinflammatoryproperties 113-114 and are used as potent antidiabetic agents. 115-116 Inaddition, the pharmacological and antitumor activities of many compounds containingpyrazoline rings have been reviewed. 117-119 Pyrazolines can be synthesized from α, β-unsaturated carbonyl compounds and hydrazines. They are reported to be potentialextractants and powerful drugs. 120 The chemistry of pyrazoline was reviewed by Jorbein 1967, which have been studied extensively for their biodynamic behaviour121 andindustrial applications. 122SYNTHETIC ASPECTS1. Pechmann H. V. 123 has synthesized pyrazoles (I) by the reaction of acetylenesand diazomethane.+HCCH H 2 C N + N -(I)NNH2. Knorr L. 124 has synthesized two structurally isomeric pyrazoles (II), (III) bythe condensation of substituted hydrazines with 1,3-dicarbonyl compounds.RRR 2OR 1R 1RH 2 N NHN N1 + + + H 2 OArON NRR 2RAr Ar2(II)(III)3. Perumal P.T. et.al. 125 have synthesized pyrazoles (IV) by the reaction ofhydrazones with Vilsmeier reagent.Pyrazolines…

Studies on some compounds… 114C 6 H 3 (NO 2 ) 2N NC 6 H 3 (NO 2 ) 2NNHDMF-POCl 3H 5 C 670-80 0 C /4h.H 5 C 6CO 2 CH 2 C 6 H 5CO 2 CH 2 C 6 H 5(IV)4. By the microwave assisted cyclocondensation of hydrazine derivatives withalkyl dihalides 126 (V).RK 2CO 3,H 2O+ X X NMWNHNH 2 R(V)N5. Boruah R.C.et al. 127 suggested one pot synthesis of pyrazoles (VI) from β-Formylenamides.R 2OHCR 1NHACNH 2OH, HClKH 2PO 4R 2N(VI)NR 1Ac6. Marica Theiszova et al. 128 have synthesized pyrazoles by condensation of 2-ethoxymethylene-3-oxobutanenitrile and hydrazines.7. 2-Pyrazolines (VII) can be constructed by the cyclocondensation of chalconeswith hydrazine hydrate. 129OR 1R R 1+ NH 2 .NH 2 .H 2 O R N(VII) HNPyrazolines…

Studies on some compounds… 1158. 2-Pyrazolines can be prepared by condensation of Chalcone dibromide withhydrazines. 1309. Epoxidation of chalcones gave epoxy ketones which reacts with hydrazine andphenyl hydrazine to give pyrazolines. 13110. 2-Pyrazolines (VIII) can be prepared by cyclocondensation of γ-ketosulfonewith refluxing hydrazines and KOH/methanol under nitrogen condition.132R 1OSON H 2NHRNRNOKOH, Methanolreflux N 2(VIII)11. Dipolar Cycloaddition of nitrileimines of dimethyl fumarate, fumaronitrile and133the N-aryl maleimides yielded the corresponding pyrazolines.12. Epoxidation of chalcones with epoxy ketones on reaction with hydrazinehydrate and phenyl hydrazine to give pyrazolines. 134REACTION MECHANISMRRO .. C CH -C +CH -H 2 N NH R 2O CH R 1Proton transfer HO CH R 1R R 1H N N +2 HH N N +2 H(I)(II) R 2 R 2RRNCNCH 2CHR 1-H 2 ORHO CHNNCH 2CHR 1C CH 2O CH R 1H 2 N NR 2R 2(V)R 2(IV)(III)Pyrazolines…

Studies on some compounds… 116The above mechanism seems to be operable for the condensation of chalconeswith hydrazines. 135Nucleophillic attack by hydrazine at the β-carbon of the α, β-unsaturatedcarbonyl system (I) forms species (II), in which the negative charge is mainlyaccommodated by the electronegative oxygen atom. Proton transfer from the nitrogento oxygen produces an intermediate end which simultaneously ketonises to ketoamine(III). Another intramolecular nucleophillic attack by the primary amino group ofketoamine on its carbonyl carbon followed by proton transfer from nitrogen to oxygenleads ultimately to hydroxyl amine (IV). The later with a hydroxy group and aminegroup on the same carbon loses water easily to yield the pyrazolines (V).THERAPEUTIC IMPORTANCE OF PYRAZOLINESCompounds with a pyrazole structure are known to possess monoamineoxidase nhibitor 136 , antibacterial 137 , antidepressant 138 , hypotensive 139 , antipyretic andanti- inflammatory 140activities. Pyrazolines, bicyclic pyrazolines are nitrogencontaining heterocyclic compounds are well known for their pronounced antiinflammatoryactivity. 141-149 These compounds have been developed as nonsteroidalanti-inflammatory drugs. They block the formation of prostaglandins and havinganalgesic, antipyretic and anti-inflammatory activity.150 The discovery of this class ofdrugs provides an outstanding case history of modern drug development and alsopoints out the unpredictability of biological activity from structural modification of aprototype drug molecule.From the literature survey, it was revealed that 2-pyrazolines are bettertherapeutic agents. Some of the activities are mentioned below.1. Antiallergic. 1512. Anticonvulsant. 151,1523. Antiimplantation. 1534. Antiinflammatory. 1545. Antitumor. 1556. Antineoplastic. 1577. Antimicrobial. 1588. Analgesic. 159,1609. Bacteriocidal. 161,16210. Cardiovascular. 163Pyrazolines…

Studies on some compounds… 11711. Diuretic. 16412. Fungicidal. 16513. Hypoglycemic. 16614. Tranquilizer. 167Untawy, Atif and coworkers 168 have patented 3-Methyl-4'-(substituted phenylazo)-pyrazol-5-ones as antibacterial agent. K. Satyanarayana and MNA Rao 169synthesized some 4-[5-(substituted aryl)-4,5-dihydro-lH-pyrazol-3-yl]-3-phenylsydnones (VI) as anti-inflammatory, antiarthritic and analgesic agents. Essa H. Hu etal. 170have synthesized some pyrazoline derivatives (VII) of anthranilic acid andreported them as anti-inflammatory agents.COOHNNCOCH 3NHN NSNHRR= p-OCH 3-C 6H 4R=p-OH-C 6H 4R=-C 6H 5(VI)HNRNNNOO -(VII)Parikh et. al. 171 have synthesized some antimicrobial pyrazolines. ShivanandaM. K. and co-workers 172 have prepared substituted pyrazolines and reported theirantibacterial activity. Guniz Kacukguzel et al. 173 have synthesized pyrazolines as aantimicrobial and anticonvulsant agents. Gulhan T. Z. and co-workers 174 haveprepared pyrazolines as a hypotensive agent. Nisha Singh and co-workers 175 havePyrazolines…

Studies on some compounds… 118synthesized 1- acetyl pyrazolines (VIII) and reported them as potent pesticides andfungicides.OHNNOCH 3(VIII)ArE. Palaska et al. 176 have prepared 3,5- diphenyl-2-pyrazolines (IX) and citedtheir antidepressant activity. Malhotra V. et al. 177 have synthesized new pyrazolines asa cardiovascular agents (X).R 1N NHR 2OMeR 1=H,Cl,Br,Me,OMeOMePhR 1N NS(X)R NH 2R 2=H,Cl(IX)R 1=R 2=ArylTejas Upadhyay et. al. 178 and Sohit Rajvaidya et. al. 179 have preparedpyrazolines as antimicrobial agent. Ashok Kumar et al.180 have synthesizedpyrazolines as anticonvulsant agents (XI).SHNNHOO(XI)N N OC H 3OMePyrazolines…

Studies on some compounds… 119A. V. Dobaria and co-workers 181 have discovered pyrazolines bearingchloroquinoline nucleus as antimicrobial agents (XII). Berghot M. A. et. al. 182 haveprepared some pyrazoline derivatives of diazepam having antibacterial activityRNHNC H 3NClR=Aryl(XII)Ahn J. H. et. al. 183 have described the synthesis of cyano-pyrazolinederivatives as potent antidiabetic agents (XIII) and DP-IV inhibitor activity. Jeong T.S. et. al. 184 have synthesized some novel 3,5-diaryl pyrazolines as human acyl-Co A:cholesterol acyl transferase inhibitors.NCOCNNNHNHN(XIII)NNovel analogs of linezolid (XIV) were synthesized by Stan D. Andrea,et. al. 185and evaluated their antibacterial activity.ONNFN(XIV)ONHAcY. Rajendra Prasad et. al. 186 have synthesized some 1,3,5-triphenyl-2-pyrazolines and 3-(2’-hydroxy naphthalen-1’-yl)-1,5-diphenyl-2-pyrazolines andreported as antidepressant (XV) & (XVI).Pyrazolines…

Studies on some compounds… 120R 3R 4R 2R 3R 1R 2NNNR 1R 4NOH(XV)R 1 , R 2 , R 3 , R 4 = Alkyl(XVI)1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines (XVII) weresynthesized by Gulberk Ucar et al. 187 A novel cholinesterase and selective monoamineoxidase B inhibitors for the treatment of Parkinson’s and Alzheimer’s diseases.SRN(XVII)NSNHR 1Fedele Manna 188 and co workers synthesized substituted pyrazoline (XVIII)and evaluated for their anticancer activity and for their ability to inhibit P-glycoprotein mediated multidrug resistance by direct binding to a purified proteindomain containing an ATP-binding site and a modulator interacting region.H 3 CO(XVIII)NNH 3 COD. G. Jones et al. 189 have synthesized pyrazoline derivative (XIX) whichpossessing PR antagonist activity. Amir Azam and co-workers 190 have synthesizedPyrazolines…

Studies on some compounds… 121some 1-N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives (XX) andtested their antiamoebic activity.H 3CCH 3NNNOSONNClSRR= Cyclic amineClCl(XIX) (XX)Mohammad Abid and Amir Azam 191have synthesized 1-(thiazolo-[4,5-b]quinoxalin-2-yl)-3-phenyl-2-pyrazoline derivatives (XXI) and reported asantiamoebic agent. John R. Goodell. et al. 192 have synthesized novel 1,3,5-trisubstituted pyrazoline derivative which shows anti westnile virus activity (XXII).H 3 CNNNSNNSNNOClCl(XXI)(XXII)NO 2Abd El-Galil E. Amr et. al. 193 synthesized a series of androstano [17,16c]pyrazolines (XXIII). The compounds were evaluated for their antiandrogenic activitycompared to that of Cyproterone.NNCH 3H 3 CHHHHCH 3H Ar CH 3R(XXIII)Pyrazolines…

Studies on some compounds… 122M. Shaharyar et al. 194 the pyrazolines (XXIV) were synthesized and tested fortheir antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv(MTB) and INH-resistant M. tuberculosis. (INHR-MTB).NC H 3OHONRN(XXIV)Richard A. Nugent,et al. 197 synthesize pyrazoline bisphosphonate esters(XXV) which showed novel anti-inflammatory activity and are capable of inhibitingchronic arthritis and inflammation in animals. Such compounds might be useful inman for treating chronic issue injury associated with arthropathies such asinflammatory joint disease as well as other chronic inflammatory diseases. A novelpyrazoline (XXVI) compound that has potent cerebroprotective effects in the rat focalcerebral ischemia model was discovered by H. Kawazural,et al. 195 David M. Fergusonand Pei-Yong Shi. 196 Synthesized Triaryl pyrazoline {[5-(4-chloro-phenyl) – 3 –thiophen – 2 – yl-4,5-dihydro pyrazol-1-yl] -phenyl-methanone}(XXVII) inhibitsflavivirus infection in cell culture. The inhibitor was identified through highthroughputscreening of a compound library using a luciferase-expressing West Nile(WN) virus infection assay.ClEtOEtOEtOEtOOPPONHNOFNH 3CNNOONNS(XXV) (XXVI) (XXVII)Pyrazolines…

Studies on some compounds… 123Drug molecules having pyrazole nucleus with good pharmacological activitiesare listed below.CH 3C-N +ONH NNNCH 3ONCH 3NCH 3NCF 3Zaleplon[Diabetic agent][Sedative, Hypnotic]NCF 3CH 3NCH 3CNNNH 2 NO 2 SCelecoxibAnti-inflammatoryPNU-32945[HIV-1Reversetranscriptaseinhibitor]N H 2NNH 2NNNONNOH 2 C(H 2 C) 3OZonipiride[Sodium ion exchanger]Oxyphenbutazone[Antiarthritic]CH 3CH 3ArNNNNN[Antitumor agent]NNNHCH 3HHHStanozolol[Insecticide]HCH 3Pyrazolines…

Studies on some compounds… 124With an intention of preparing the compounds possessing better therapeuticactivity, we have undertaken the synthesis of pyrazoles which have been described infollowing sections.SECTION:-3.2: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO-N-[3-{3-ARYL-1[H]PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.SECTION:-3.3: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3 - DICHLORO-N- [3- {3- (ARYL)-1-PHENYL - 1[H]PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.SECTION:-3.4: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3- DICHLORO-N– [3- {3- (ARYL)- 1- ACETYL - 1[H]PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.SECTION-3.5: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO-N – [3-{3-(ARYL)-1-THIOCARBAMIDO –1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.Pyrazolines…

Studies on some compounds… 125SECTION-3.1SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3 -DICHLORO N-(3-SUBSTITUTED STYRYL CARBONYL) BENZAMIDE.With the biodynamic activities of chalcones and as a fine synthon for differentheterocyclic rings, the awareness has been paying attention on the creation of newchalcones. With a observation to obtained compounds having better therapeuticactivity, we have synthesized 2,3–dichloro-N-(3-substituted styryl carbonyl)benzamide of Type-(IV) by the condensation of N-(3-acetylphenyl)-2,3-dichlorobenzamide with various aromatic aldehydes by using alkali as catalyst.ClClOOHNCH 3R-CHO Ethanol / NaOHCompound-(IV)Type-(IV)ClClONHORThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (IVa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (IVa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations.Selected compounds have been also screened for their antitubercular activity,(Chapter-8).Pyrazolines…

Studies on some compounds… 126Reaction SchemeClClCl+H 2NCH 3OOTolueneTEAClClOOHNCH 3Ethanol / NaOHR-CHOClClOORNHR= ArylType – (IV)Pyrazolines…

Studies on some compounds… 127IR SPECTRAL STUDIES OF 2,3 -DICHLORO N-(3-(p-METHOXY STYRYLCARBONYL) BENZAMIDE.105%T907560453015Cl3213.513049.56ClONH2835.45O2359.02OCH 31660.771595.181585.541550.821514.171438.941417.731319.351292.351249.911174.691143.831053.17979.87937.44821.70790.84738.76545.8704000 3600MM-013200280024002000180016001400120010008006004001/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2970 2975-2950 198-CH3 C-H str. (sym) 2835 2880-2860 "C-H def. (asym.) 1417 1470-1435 "C-H def.(sym.) 1319 1390-1370 "Aromatic C-H str. 3049 3090-3030 199C=C str. 1550 1540-1480 "C-H i.p. def. 1053 1070-1000 "C-H o.o.p. def. 821 835-810 "Moiety C-Cl (str.) 790 800-600 200Carboxamide -CONH- 1660 1700-1650 201Ether C-O-C str. 1249 1260-1200 "Vinyl CH=CH 3049 3050-3000 "Chalcone C=O str 1620 1685-1640 "Pyrazolines…

Studies on some compounds… 128PMR SPECTRAL STUDIES OF 2,3 -DICHLORO N-(3-(p-METHOXYSTYRYL CARBONYL) BENZAMIDE.ghCH 3ClClOOaOeg'h'bcNHd'fdInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 3.85 3H Singlet Ar-OCH 32 6.94 2H doublet -CH=CH-(venyl)3 7.22-7.42 4H Double dolublet Ar-Hg,g’,h,h’4 7.40-7.78 5H multiplet Ar-Ha,b,c,e,f5 7.80-7.82 2H doublet Ar-Hd, d’6 8.25 1H singlet -NH (-NHCO)Pyrazolines…

Studies on some compounds… 129MASS SPECTRAL STUDIES OF 2,3-DICHLORO-N-[3-{3-(p-METHOXYPHENYL)-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.ClClONHOOCH 3m/z = 426.29Pyrazolines…

Studies on some compounds… 130MASS FRAGMENTATIONClClOCl ClOOOOCH+3 0NHNH 2 0NHm/z = 341m/z = 308Cl+0CH 3+OO +0Cl ClOOOHNONHOm/z = 259NHm/z = 426( M. I. P.) = (B. P.)m/z = 327(M+1)+2)Cl ClCl ClOO +O + O +H 2 NNHm/z = 190+OH+0m/z = 174m/z = 145m/z = 319Pyrazolines…

Studies on some compounds… 132[C] BIOLOGICAL EVALUATION OF 2,3-DICHLORO N-[3-(SUBSTITUTED STYRYL)CARBONYL] BENZAMIDE.Antimicrobial testing were carried out as described in Chapter-8, The zones ofinhibition of test solutions are recorded in Graphical Chart-4a, Table-4a. Page. No.-366, 367. Result and discussion is given on page no.:-368.Pyrazolines…

Studies on some compounds… 133● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Pyrazolines…

Studies on some compounds… 134SECTION-3.2SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N- {3-[3-ARYL-1[H] PYRAZOLINE-5-YL} PHENYL] BENZAMIDE.Pyrazoline derivatives represent one of the most active classes of compoundshaving a wide spectrum of biological activities. Looking to the interesting propertiesof pyrazolines it was considered worthwhile to synthesize a series of pyrazolines ofType- (V) for obtaining biologically potent agents which were prepared by reactingchalcones of Type-(IV) with hydrazine hydrate in Ethanol.ClClOORNHEthanolNH 2 NH 2 .H 2 OClClCompound-(V)ORType-(V)HNNNHThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (Va-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (Va-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations,Selected compounds have been also screened for their antitubercular activity.(Chapter-8)Pyrazolines…

Studies on some compounds… 135Reaction schemeClClHNOOCH 3+HONaOHEthanolClClOORNHNH 2 NH 2 . H 2 OEthanolClClORHNNNHR= ArylType-(V)Pyrazolines…

Studies on some compounds… 136IR SPECTRAL STUDIES OF 2,3-DICHLORO-N-[3-{3-(p-METHOXYPHENYL)- 1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.105%T90752933.832835.45935.51H 3 C604530ClClHNONNHO2360.951676.201651.121602.901514.171492.951417.731348.291301.991247.991174.691030.02829.42788.91150682.824000 3600MM-023200280024002000180016001400120010008006004001/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2933 2975-2950 198-CH3 C-H str. (sym) 2835 2880-2860 "C-H def. (asym.) 1492 1470-1435 "C-H def.(sym.) 1348 1390-1370 "Aromatic C-H str. 3075 3090-3030 199C=C str. 1515 1540-1480 "C-H i.p. def. 1030 1125-1000 "C-H o.o.p. def. 829 835-810 "Moiety C-Cl (str.) 788 800-600 200Carboxamide -CONH- 1651 1700-1650 201Ether C-O-C str. 1247 1260-1200 "Pyrazole ring C-N (str) 1174 1230-1020 "N-H (str) 3330 3320-3140 "C=N (str) 1602 1650-1550 "C-H (CH 2 ) str. 2835 2850-2790 "Pyrazolines…

Studies on some compounds… 137PMR SPECTRAL STUDIES OF 2,3-DICHLORO-N-[3-{3-(p-METHOXYPHENYL)-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.ClClHNOHbHaHcH 3CNNHOInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 3.25 1H Double doublet -CH a2 3.52 1H Double doublet -CHb3 3.94 1H singlet -OCH 34 5.12 1H triplet -CH X5 6.81-7.62 11H multiplet Ar-H6 7.38 1H singlet -NH (pyrazo.)overlapped7 7.98 1H singlet -NH (-NHCO)Pyrazolines…

Studies on some compounds… 138MASS SPECTRAL STUDIES OF 2,3-DICHLORO-N-[3-{3-(p-METHOXYPHENYL)-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.ClClH 3 COOHNNHNm/z = 440.32Pyrazolines…

Studies on some compounds… 139MASS FRAGMENTATIONH 3 CO+0ClClH 3 CO+0N H 2NNHHNOCH 2+NH 2+m/z = 268m/z = 321Nm/z = 134ClC H 3O+0+0ClOClClNm/z = 103HNNNHHNO+CH 2 0NH 2ClClO ++m/z = 440( M. I. P.) = (B. P.)(m+1)+2ClCH 2H 2 NNH 2m/z = 307+0m/z = 174Cl+0m/z = 148m/z = 135Pyrazolines…

Studies on some compounds… 140EXPERIMENTALSYNTHESIS AND STRUCURE ELUCIDATION OF 2,3-DICHLORO-N-[3-{3-ARYL-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATIONOFN-(3-ACETYLPHENYL)-2,3-DICHLOROBENZAMIDE.Pls. refer chapter -3, Section-3.1, Page No.131[B] PREPARATION OF 2,3-DICHLORO N-[3-(4-METHOXYSTYRYL)CARBONYL] BENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[C] PREPARATION OF 2,3-DICHLORO-N-[3-{3-(4-METHOXYPHENYL)-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.A mixture of 2,3-dichloro-N-[3-(4-methoxy styryl) carbonyl] benzamide (4.26gm, 0.01 mole) and hydrazine hydrate (1.0 gm, 0.02 mole) in 25 ml ethanol wasrefluxed on an oil-bath for 10-11 hrs. The solution was poured on crushed ice. Theproduct was isolated and crystallized from dioxane. Yield-65%, m.p.-116 0 C;(C 23 H 19 Cl 2 N 3 O 2 ; required: C, 62.74; H, 4.35; N, 9.54%; found: C, 62.71; H, 4.37; N,9.44%).Similarly, other 2,3-Dichloro-N-[3-{3-(aryl)-1[H]pyrazoline-5-yl}phenyl]benzamide were prepared. The physical constants are recorded in Table-5.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8).Pyrazolines…

Studies on some compounds… 141[D] BIOLOGICAL EVALUATION 2,3-DICHLORO-N-[3-{3-(ARYL)-1[H]PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.Antimicrobial testing were carried out as described in Chapter-8, The zones ofinhibition of test solutions are recorded in Graphical Chart-5a, Table-5a. Page No.-369, 370.Result and discussion is given on page no.:- 371.Pyrazolines…

Studies on some compounds… 142● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Pyrazolines…

Studies on some compounds… 143SECTION-3.3SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO-N–[3-{3-(ARYL)-1-PHENYL-1[H] PYRAZOLINE– 5-YL} PHENYL] BENZAMIDE.Looking to the interesting therapeutic activities of pyrazoline, it wasconsidered worthwhile to synthesize compounds bearing N-(3-acetylphenyl)-2, 3-dichlorobenzamide moiety linked to the pyrazoline nucleus. Pyrazoline of Type (VI)have been prepared by the action of chalcones of Type-(IV) with phenyl hydrazine inpresence of ethanolic sodium hydroxide.ClClOORNHClEthanol C 6 H 5 -NHNH 2NaOHClCompound-(VI)(Type-(VI)HNONRNC 6 H 5The structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (VIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (VIa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations,Selected compounds have also been screened for their antitubercular activity(chapter-8).Pyrazolines…

Studies on some compounds… 144Reaction schemeClClHNOOCH 3+HONaOHEthanolClClOORNHClC 6 H 5 -NHNH 2EthanolNaOHClORHNNNC 6H 5R= ArylType-(VI)Pyrazolines…

Studies on some compounds… 145IR SPECTRAL STUDIES OF 2,3-DICHLORO-N-{3-[3-(p-METHOXYPHENYL)-1-PHENYL-1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.105%T90753234.733061.132951.192835.45931.65879.5760453015ClClHNO2359.02H 3 CONN1660.771595.181550.821502.601413.871386.861319.351247.991174.691130.321031.95840.99788.91748.4104000 3600MM-043200280024002000180016001400120010008006004001/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2951 2975-2950 198-CH3 C-H str. (sym) 2835 2880-2860 "C-H def. (asym.) 1413 1470-1435 "C-H def.(sym.) 1386 1390-1370 "Aromatic C-H str. 3061 3090-3030 199C=C str. 1502 1540-1480 "C-H i.p. def. 1031 1125-1000 "C-H o.o.p. def. 840 835-810 "Moiety C-Cl (str.) 788 800-600 200Carboxamide -CONH- 1660 1700-1650 201Ether C-O-C str. 1247 1260-1200 "Pyrazole ring C-N (str) 1174 1230-1020 "C=N (str) 1595 1650-1550 "C-H (CH 2 ) str. 2835 2850-2790 "N-Ph 1502 1507-1495 "Pyrazolines…

Studies on some compounds… 146PMR SPECTRAL STUDIES OF 2,3-DICHLORO -N- {3-[3-(p-METHOXYPHENYL)-1-PHENYL -1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDEH 3 COClClHNOHbHaNNHxInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 3.18 1H Double doublet -CH A2 3.82 1H Double doublet -CH B3 3.68 1H singlet -OCH 34 5.45 1H triplet -CH X5 6.62-7.82 16H multiplet Ar-H6 8.22 1H singlet -NH (NHCO)Pyrazolines…

Studies on some compounds… 147MASS SPECTRAL STUDIES OF 2,3-DICHLORO-N –[3-{3-(p-METHOXYPHENYL)-1-PHENYL - 1[H]PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.ClH 3 CClOONHNNm/z = 516.41Pyrazolines…

Studies on some compounds… 148MASS FRAGMENTATIONClClClHNONH+NH 0ClHNOHN+0Mc Laffertyrearrangementm/z = 370m/z = 488ClClClClHNON N OCH 3+0m/z = 516( M. I. P.)m/z = 174O +N NH 2 NOm/z = 342CH 3+0O CH 3+ OH + O000+CH 3+NNm/z = 108m/z = 77m/z = 134m/z = 120Pyrazolines…

Studies on some compounds… 149EXPERIMENTALSYNTHESIS AND STRUCURE ELUCIDATION OF 2,3-DICHLORO-N-[3-{3-(ARYL)-1-PHENYL-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF N-(3-ACETYLPHENYL)-2,3-DICHLOROBENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[B] PREPARATION OF 2,3-DICHLORO N-[3-(4-METHOXYSTYRYL)CARBONYL] BENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[C] PREPARATION OF 2,3-DICHLORO-N-{3-[3-(4-METHOXYPHENYL)-1-PHENYL - 1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.A mixture of 2,3-dichloro-N-[3-(4-methoxy styryl) carbonyl] benzamide (4.26gm, 0.01 mole) and phenyl hydrazine (2.16 gm, 0.02 mole) in acetic acid as a solventwas refluxed on an oil-bath for 5-6 hrs. The solution was poured on crushed ice. Theproduct was isolated and crystallized from DMF-ethanol. Yield-71%, m.p.-196 0 C;(C 29 H 23 Cl 2 N 3 O 2 ; required: C, 67.45; H, 4.49; N, 8.14%; found: C, 67.43; H, 4.42; N,8.11%).Similarly, other 2,3-dichloro-N- {3-[3-(aryl)-1-phenyl - 1[H] pyrazoline – 5 -yl} phenyl] benzamide were prepared. The physical constants are recorded inTable-6.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)Pyrazolines…

Studies on some compounds… 150[D] BIOLOGICAL EVALUATION OF 2,3-DICHLORO-N-[3-{3-(ARYL)-1-PHENYL-1[H] PYRAZOLINE-5-YL}PHENYL] BENZAMIDE.Antimicrobial testing were carried out as described in Chapter-8. The zones ofinhibition of test solutions are recorded in Graphical Chart-6a, Table-6a. Page No.-372, 373. Result and discussion is given on page no.:- 374.Pyrazolines…

Studies on some compounds… 151● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Pyrazolines…

Studies on some compounds… 152SECTION-3.4SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N –[3-{3-(ARYL)-1-ACETYL-1[H]PYRAZOLINE–5-YL}PHENYL]BENZAMIDE].Pyrazolines play a vital role owing of their wide range of biological activityand with an aim to getting better drug, it was considered worthwhile to synthesizesome new acetyl pyrazolines. The preparation of 2,3-dichloro-N –[3-{3-(aryl)-1-acetyl - 1[H] pyrazoline–5-yl}phenyl]benzamide] Type (VII) have been undertakenby cyclo condensation of chalcones of Type (IV) with hydrazine hydrate in glacialacetic acid.ClClOORNHClNH 2 NH 2 . H 2 Ogl. acetic acidClCompound-(VII)Type-(VII)HNONRNCOCH 3The structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (VIIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (VIIa-j) have been compared with standarddrugs viz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(chapter-8).Pyrazolines…

Studies on some compounds… 153Reaction SchemeClClHNOOCH 3+HONaOHEthanolClClOORNHNH 2NH 2. H 2Ogl.acetic acidClClORHNNNCOCH 3R= ArylType – (VII)Pyrazolines…

Studies on some compounds… 154IR SPECTRAL STUDIES OF 2, 3-DICHLORO- N –[3-{3-(p-METHOXYPHENYL)-1-ACETYL-1[H]PYRAZOLINE–5-YL} PHENYL] BENZAMIDE].105%T9075604530153086.212839.31ClClHNO2360.95C H 3NNOOCH 31676.201637.621606.761550.821516.101452.451413.871359.861323.211301.991247.991178.551033.88956.72829.42796.6304000 3600MM-033200280024002000180016001400120010008006004001/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2930 2975-2950 198-CH3 C-H str. (sym) 2839 2880-2860 "C-H def. (asym.) 1452 1470-1435 "C-H def.(sym.) 1359 1390-1370 "Aromatic C-H str. 3086 3090-3030 199C=C str. 1516 1540-1480 "C-H i.p. def. 1033 1125-1000 "C-H o.o.p. def. 829 835-810 "Moiety C-Cl (str.) 796 800-600 200Carboxamide -CONH- 1676 1700-1650 201Ether Ar-O-C (sym.) 1045 1075-1010 "Pyrazole ring C-N (str) 1178 1230-1020 "C=N (str) 1606 1650-1550 "C-H (CH 2 ) str. 2839 2850-2790 "N-COCH 3 1637 1660-1650 "Pyrazolines…

Studies on some compounds… 155PMR SPECTRAL STUDIES OF 2, 3-DICHLORO-N – [3-{3-(p-METHOXYPHENYL)-1-ACETYL-1[H] PYRAZOLINE– 5 -YL} PHENYL] BENZAMIDE].H 3 COClClHNOHbHaHxONNCH 3Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 2.41 1H singlet -COCH 32 3.14 1H Double doublet -CH A3 3.84 1H Double doublet -CH B4 3.78 1H singlet -OCH 35 5.50 1H triplet -CH X6 6.68-7.80 11H multiplet Ar-H7 8.28 1H singlet -NH (-NHCO)Pyrazolines…

Studies on some compounds… 156MASS SPECTRAL STUDIES OF 2, 3-DICHLORO- N – [3-{3-(p-METHOXYPHENYL)-1-ACETYL-1[H] PYRAZOLINE–5 -YL} PHENYL] BENZAMIDE].ClC H 3OClHNONNOCH 3m/z = 482.35Pyrazolines…

Studies on some compounds… 157MASS FRAGMENTATIONClClClHNONH+NH 0ClHNOHNOCH 3+0C H 3m/z = 455OMc Laffertyrearrangementm/z = 337ClClClClClONHNm/z = 440ClONHNN HN HOCH 3OH+0+0+0ClClOHNOCH 3m/z = 482( M. I. P.) = (B. P.)OCH 3ONNHNN N CH 3 0O++O+m/z = 174CH 3O +N N CH 30 H 2NOm/z = 309m/z = 426m/z = 385+O0CH 3m/z = 108Pyrazolines…

Studies on some compounds… 158EXPERIMENTALSYNTHESIS AND STRUCURE ELUCIDATION OF 2, 3-DICHLORO- N – [3-{3-(ARYL)-1-ACETYL-1[H] PYRAZOLINE–5-YL} PHENYL] BENZAMIDE.]Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATIONOFN-(3-ACETYLPHENYL)-2,3-DICHLOROBENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[B] PREPARATION OF 2,3-DICHLORO N-[3-(4-METHOXYSTYRYL)CARBONYL] BENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[C] PREPARATION OF OF 2, 3-DICHLORO- N – [3-{3-(ARYL)-1-ACETYL-1[H]- PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE].A mixture of 2,3-dichloro-N-[3-(4-methoxy styryl) carbonyl] benzamide (4.26gm, 0.01 mole) and hydrazine hydrate (1 gm, 0.02 mole) in presence of glacial aceticacid on an oil-bath for 7-8 hrs. The solution was poured on crushed ice. The productwas isolated and crystallized from dioxane. Yield-70, m.p.-245 0 C; (C 25 H 21 Cl 2 N 3 O 2 ;required: C, 62.25; H, 4.39; N, 8.71 %; found: C, 62.22; H, 4.44; N, 8.75 %).Similarly, other 2, 3-dichloro-N- {3-[3-(aryl)-1-phenyl - 1[H] pyrazoline – 5 -yl}-phenyl] benzamide were prepared. The physical constants are recorded inTable-7.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8).Pyrazolines…

Studies on some compounds… 159[C] BIOLOGICAL EVALUATION 2,3-DICHLORO-N–[3-{3-(ARYL)-1-ACETYL -1[H]- PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE].Antimicrobial testing were carried out as described in Chapter-8. The zones ofinhibition of test solutions are recorded in Graphical Chart-7a, Table-7a. Page No.-375, 376. Result and discussion is given on page no.: - 377.Pyrazolines…

Studies on some compounds… 160● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Pyrazolines…

Studies on some compounds… 161SECTION-3.5SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N –[3-{3-(ARYL)-1-THIOCARBAMIDO - 1[H] PYRAZOLINE – 5 - YL} PHENYL]BENZAMIDE.Pyrazolines are endowed with multipurpose biological activities. Lookingat their versatile therapeutic importance and with an aim to getting better drug, it wasconsidered worthwhile to synthesize some new pyrazole of Type (VIII). Thepreparation of pyrazolines of type (VIII) have been under taken by cyclocondensationof 2,3-dichloro-N-[3-(4-methoxy styryl) carbonyl] benzamide with thiosemicarbezide.ClClOORNHClNH 2 CSNHNH 2EthanolNaOHClORSCompound-(VIII)Type-(VIII)HNNNNH 2The structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (VIIIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (VIIIa-j) have been compared with standarddrugs viz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(chapter-8).Pyrazolines…

Studies on some compounds… 162Reaction SchemeClClHNOOCH 3+HONaOHEthanolClClOORNHNH 2 CSNHNH 2EthanolNaOHClClORSHNNNNH 2R= ArylPyrazolines…

Studies on some compounds… 163IR SPECTRAL STUDIES OF 2,3-DICHLORO-N–[3-{3-(p-METHOXYPHENYL)-1-THIOCARBAMIDO - 1[H] PYRAZOLINE – 5 - YL} PHENYL]BENZAMIDE.120%T10590756045301503269.453066.92ClClHNO2360.95C H 3NNOSNH 21664.621579.751556.611483.311435.091354.071251.841161.191080.17976.01881.50-154000 3600MM-053200280024002000180016001400120010008006004001/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2930 2975-2950 198-CH3 C-H str. (sym) 2865 2880-2860 "C-H def. (asym.) 1435 1470-1435 "C-H def.(sym.) 1354 1390-1370 "Aromatic C-H str. 3066 3090-3030 199C=C str. 1540 1540-1480 "C-H i.p. def. 1080 1125-1000 "C-H o.o.p. def. 830 835-810 "Moiety C-Cl (str.) 710 800-600 200Carboxamide -CONH- 1664 1700-1650 201Ether C-O-C (sym.) 1251 1260-1200 "Pyrazole ring C-N (str) 1161 1230-1020 "C=N (str) 1579 1650-1550 "C-H (CH 2 ) str. 2830 2850-2790 "C=S 1556 1590-1550 "-NH str 3269 3320-3140 "Pyrazolines…

Studies on some compounds… 164PMR SPECTRAL STUDIES OF 2,3-DICHLORO-N–[3-{3-(p-METHOXYPHENYL)-1-THIOCARBAMIDO - 1[H] PYRAZOLINE – 5 - YL} PHENYL]BENZAMIDE.H 3 COClClHNOHbHaHxSNNNH 2Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 3.20-3.22 1H Double doublet -CH A2 3.40-3.44 1H Double doublet -CH B3 3.81 1H singlet -OCH 34 5.98 1H Double doublet -CH X5 6.81-7.68 11H multiplet Ar-H6 7.98 2H Singlet (Broad) -NH 27 8.25 1H singlet -NH (-NHCO)Pyrazolines…

Studies on some compounds… 165MASS SPECTRAL STUDIES OF 2,3-DICHLORO-N–[3-{3-(p-METHOXYPHENYL)-1-THIOCARBAMIDO - 1[H] PYRAZOLINE – 5 - YL} PHENYL]BENZAMIDE.ClClC H 3OHNONNSNH 2M/Z= 499.42Pyrazolines…

Studies on some compounds… 166MASS FRAGMENTATIONClClClSClHNONN H+0HNONH 2N N OH+0m/z = 334m/z = 483HO+0ClClOHNNN H0CH 3O+ClClOHNSNH 2+N N CH 30OHNNONHm/z = 440m/z = 499( M. I. P.) = (B. P.)ClCl+0OCH 3+0ClO+m/z = 426m/z = 108NH 2m/z = 155m/z = 78Pyrazolines…

Studies on some compounds… 167EXPERIMENTALSYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO- N – [3-{3-(ARYL)-1-THIOCARBAMIDO - 1[H] PYRAZOLINE – 5 - YL} PHENYL]BENZAMIDE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF N-(3-ACETYLPHENYL)-2,3-DICHLOROBENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[B] PREPARATION OF 2,3-DICHLORO N-[3-(4-METHOXYSTYRYL)CARBONYL] BENZAMIDE.Pls. refer chapter-3, Section-3.1, Page No.131[C] PREPARATION OF 2,3-DICHLORO-N–[3-{3-(ARYL)-1-THIOCARBAMIDO-1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.A mixture of 2,3-dichloro-N-[3-(4-methoxy styryl) carbonyl] benzamide (4.26gm, 0.01 mole) and thiosemicarbazide (0.04 mole) in presence of ethanolic sodiumhydroxide on an oil-bath for 10-11 hrs. The solution was poured on crushed ice. Theproduct was isolated and crystallized from dioxan. Yield-65%, m.p.-144 0 C;(C 22 H 19 N 3 O 4 ; required: C, 57.72; H, 4.04; N, 11.22 %; found: C, 57.82; H, 4.11; N,11.25%).Similarly, other 2, 3-dichloro-N- {3-[3-(aryl)-1-phenyl - 1[H] pyrazoline – 5 -yl} phenyl] benzamide were prepared. The physical constants are recorded inTable-8.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)Pyrazolines…

Studies on some compounds… 168[C] BIOLOGICAL EVALUATION 2,3-DICHLORO-N–[3-{3-(ARYL)-1-ACETYL -1[H]- PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE].Antimicrobial testing were carried out as described in Chapter-8. The zones ofinhibition of test solutions are recorded in Graphical Chart-8a, Table-8a. Page No.-378, 379. Result and discussion is given on page no.380.Pyrazolines…

Studies on some compounds… 169● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Pyrazolines…

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Studies on some compounds… 179Biokhimiya, 36, 1201–1209 (1971).136. Gokhan N., Yesilada A., Ucar G., Erol K., Bilgin A.A.;Arch Pharm.Med.Chem. 336,362-371 (2003).137. Holla B. S., Akbarali P. M., Shivanada M. K.,IL Farmaco 55 256–263 (2000).138. Plaska E., Aytemir M., Uzbay T., Erol D.;Eur. J. Med. Chem. 36 539–543 (2001).139. Turan ZitouniG., Chevallet P., Kilic F. S.;Eur. J. Med. Chem. 35 635–641 (2000).140. Bruno O., Ranise A., Bondavalli F., Schenone F., D’Amico M., Filipelli A.,Filipelli W.,IL Farmaco 48 949–966 (1993).141. Manna F.; Chimenti F., Bolasco A., Cenicola M. L., de-Amico M. D.,ParrilloC.;Eur.J. Med. Chem. , 27, 633 (1992).142. Jain S. M., Devi S., Bani S., Singh S., Singh G. B.;Indian J. Chem. , 27B, 1019 (1988).143. Kumar A., Saxena K. K., Lata S., Saxena R. S., Srivastava V. K.;Indian Drugs 28, 111 (1990).144. Udupi R. H., Rao S. N., Bhat A. R.;Indian J. Heterocycl. Chem. 7, 217 (1998).145. Paul S., Gupta R.;Indian J. Chem. , 37B, 1279 (1998).130146. Bansal E., Srivastava V. K., Kumar A.;Eur. J. Med. Chem. 36, 81 (2001).147. Nugent R. A., Murphy M., Schlachter S. T., Dunn C., Smith R., Staite N. D.;J. Med. Chem. 36, 134 (1993).148. Krapcho J., Turk C. F.;J. Med. Chem. 22, 207 (1979).149. Warner P. L., Luber J.;U.S. Patent 4,172, 647, (1979); Chem. Abstr. 92, 58785a (1980).150. Lombardino G.;Nonsteroidal Anti-inflammatory Drugs; Wiley Interscience, John Wiley andSons: New York, 1985.151. Roman B.;Pyrazolines…

Studies on some compounds… 180Pharmazie, 45, 214 (1990).152. Brozozowsk Z., Pormarnacka E.;Acta. Pol. Pharm., 37(4), 1378-80 (1980); Chem. Abstr., 25, 80807 (1981).153. Archana Shrivastava V. K., Chandra Ramesh, Kumar Ashok;Indian J. Chem., 41B, 2371-75 (2002); Chem. Abstr., 138, 271582 (2003).154. Reddy D. B., Senshuna T. and Ramma Reddy M. V.;Indian J. Chem., 30B, 46 (1991).155. Ashok Kumar, Verma R. S. and Jagu B. P.;J. Ind. Chem. Soc., 67, 120 (1990).156. Ronald W. I., Adriano A.;Chem. Abstr., 126, 181346f (1997).157. Mokhtar H. M., Faidallah H. M.;Pharmazie, 42, 482 (1987).158. Panda J. Srinivas S. V., Rao M. E.;J. Indian Chem. Soc., 79(9), 770-1 (2002); Chem. Abstr., 138, 153499n(2003).159. Delay Francois, Patent Schrift ;Chem. Abstr., 117, 90276f (1992).160. Aysel G., Seref D., Gultaze C., Kevser E., Kamil V.;Eur. J. Med. Chem., 35, 359-64 (2000).161. Desaea P., Nunrich A., Carderny M. and Devaux G.;Eur. J. Med. Chem., 25, 285 (1990).162. Kalluraya Balakrishna, Chimabalkar R., Rai G., Gururaja R., Shenoy S.;J. Indian Coun. Chemi., 18(2), 39-43 (2001); Chem. Abstr., 138, 238061(2003).131163. Hiroyuti Y., Mocoto O. et al.;Eur. Pat. Appl. Ep 295695 (Cl. C07D 401/6) (1988); Chem. Abstr., 111, 23510(1989).164. Zalgislaw K. and Seffan A.;Acta. Pol. Pharm., 36(6), 645 (1979); Chem. Abstr., 93, 204525e (1980).165. Nayal S. S. and Singh C.P.;Asian J. Chem. 11, 1, 207-212 (1999).166. Trena K.and Zolzislaw;Acta. Pol. Pharm., 36 (3), 227 (1979); Chem. Abstr., 93, 4650r (1980).Pyrazolines…

Studies on some compounds… 181167. Hans B., Rolf R. and Rudolf R.;US. Pat. 3, 822, 283 (1974); Chem. Abstr., 81, 105494r (1974).168. Untawy, Atif E. Fatema A., Abdela M.;Chim Pharm. J., 47(1), 37-45 (1995); Chem. Abstr., 123, 228016d (1995).169. Satyanarayana K., Rao M. N. A.;Eur J Med Chem 30,641-645 (1995).170. Essa H. Hu, Daniel R. Sidler, Ulf H. Dolling;J. Org. Chem., 63, 3454-3457 (1998).171. Akhil Bhatt, Parekh H. H. and Parikh A. R.;Heterocyclic Commun., 4(4), 361-66, (Eng.); Chem. Abstr., 130, 25006x(1999).172. Shivananda M. K., Akberali P. M., Holla B., Shivarama, Shenoy M., Shalini;Org. Chem. Incl. Med. Chem. 39B(6), 440-447 (Eng.); Chem. Abstr.,134,86195n (2000).173. Guniz Kacukguzel, Sevin Rollas, Habibe Erdeniz, Muammer Kiraz, A.Cevdet Ekinci; Eur. J. Med. Chem., 35, 761-77 (2000).174. Gulhan T. Z., Pierre Chevallet, Fatma S. K., Kevser Eral.;Eur. J. Med. Chem., 35, 635-41 (2000).175. Nisha Singh; Naresh K. Sangwan, Kuldip S. Phindsa & Haisor Indra;J. Indian Chem. Soc., 78, 119-122 (2001).176. Palaska E., Aytemir M., Uzboy I. T., Erol D.;Eur. J. Med. Chem., 36(6), 539-543 (Eng), 2001; Chem. Abstr., 136, 18374v(2002).177. Malhotra V., Pathak S., Nath R., Mukherjee D., Shanker K.;Indian J. Chem., 41B, 1310-13 (2002); Chem. Abstr., 137, 370021j (2002).178. Tejas A. Upadhyay, Jawalant A. Shastri & Parekh H. H.;Orient. J. Chem., 18(1), 175-76, (2002).179. Sohit Rajvaidya, Jaladhi Vasavada & Parekh H. H.;Ind. J. Chem., 42 B, 906-908, (2004).132180. Archana V. K. Srivastava, Kumar Ashok;Arzneimittel. Forschung, 52(11), 787-91 (2002); Chem. Abstr., 138, 353758(2003).181. Dobaria A. V., Patel J. R. & Parekh H. H.;Ind. J. Chem., 42 B, 2019, (2003).Pyrazolines…

Studies on some compounds… 182182. Berghot M. A., Moawad E. B.;Eur. J. Pharm. Sci. 20(2), 173-9 (2003).183. Ahn JH, Kim HM, Jung SH, Kang SK, Kim KR, Rhee SD, Yang SD, CheonHG, Kim SS;Bioorg. Med. Chem. Letter 14(17), 4461-5 (2004).184. Jeong TS, Kim KS, An SJ, Cho KH, Lee S, Lee WS;Bioorg. Med. Chem. Letter 14(11), 2715-7 (2004).185. Stan D. Andrea, Zhizhen Barbara Zheng, Kenneth DenBleyker, Joan C.;Bioorg. & Med. Chem. Lett. 15 2834–2839 (2005).186. Y. Rajendra Prasad, A. Lakshmana Rao, L. Prasoona, K. Murali and P. RaviKumar; Bioorg. Med. Chem. letters 15(22), 5030-5034 (2005).187. Gulberk Ucar, Nesrin Gokhan, Akgul Yesilada, Altan Bilgin;Neuroscience Letters 382 327–331 (2005).188. Fedele Manna, Franco Chimenti, Rossella Fioravanti;Bioorganic & Medicinal Chemistry Letters 15 4632–4635 (2005).189. Jones D. G. et al.Bioorg. Med. Chem. Lett. 15 3203–3206 (2005).190. Amir Azam, Asha Budakoti and Mohammad Abid;E. J. Med. Chem., 41(1), 63-70 (2006).191. Mohammad Abid and Amir Azam;Bioorg. Med. Chem. letters, 16, 2812-2816 (2006).192. Goodell J. R., Pulg Basagoiti F.; Forsley B. M. et. al.;J. Med. Chem., 49, 2127-2137 (2006).193. Abd El-Galil E. Amr et al.Bioorg. Med. Chem. 14 373–384 (2006).194. Shaharyar M. et al.Bioorg. Med. Chem. Lett. 16 3947–3949 (2006).195. Kawazural H.et al.Jpn.J. pharmacol 73. 317-327 (1997).196. David M. Ferguson and Pei-Yong Shi;Antimicreobial agents and chemotherapy. 50, 1320-1329 (2006)197. Richard A. Nugent, Megan Murphy, Stephen T. Schlachter, Colin J. Dunn J.Robert; J. Med. Chem. 36, 134-139 (1993).198. V. M. Parikh; “Absorption spectroscopy of organic molecule” Additionweslay Pub. Co. London, 243, 258 (1978).Pyrazolines…

Studies on some compounds… 183199. A. R. Kartizky and R. Alan Jones;J. Chem. Soc., 294z (1960).200. F.V.Loffe;Khim. Geterokeiki Sodein, 6, 1089 (1968); Chem. Abstr., 70, 72338 (1986).201. D.L.Paria, G. M. Lampman and G. S. Kriz;Introduction to spectroscopy college publishing, Philadelphia, p-46 (1979).Pyrazolines…

CHAPTER - 4STUDIES ONPYRIMIDINE-2-THIONES

Studies on some compounds… 184INTRODUCTIONPyrimidine is the most important member of all the diazine as this ring systemoccurs widely in living organisms. Pyrimidine (I) was first isolated by Gabriel andColman in 1899. Pyrimidine and its derivatives represent one of the most active classof compounds possessing a wide spectrum of biological activities.NN(I)Pyrimidine and its derivatives have gained prominence because of theirpotential pharmaceutical values. Many pyrimidine derivatives play vital role in manyphysiological actions. They are among those molecules that make life possible asbeing some of the building blocks of DNA and RNA. Pyrimidine is considered to be aresonance hybrid of the charged and uncharged canonical structures; its resonanceenergy has been found to be less than benzene or pyridine.From pyrimidine derivatives one of the important derivative Thiopyrimidinederivatives are an important class of pharmaceutically active pyrimidine compoundsand their chemistry was extensively studied and continues to attract the attention ofsynthetic chemists. The thiopyrimidine derivatives and many heterocyclic compoundscontaining thiopyrimidine moiety are known to have major pharmacologicalactivities. In addition to various pharmacological properties, thiopyrimidines areuseful for the synthesis of tri and tetra–cyclic heterocyclic compounds.Pyrimidine is considered to be a resonance hybrid of the charged anduncharged cannonical structures; its resonance energy has been found to be less thanbenzene or pyridine.Some pyrimidines of physiologically as well as pharmacologically importanceare as under: e.g., cytosine, bedmethrin (II) and trimethoprim (III).Pyrimidine-2-thiones…

Studies on some compounds… 185ClNHONH 2O CH 3N(II)H 5 C 2NH 2NH 2N(III)NSYNTHETIC ASPECTFirst primary synthesis of thiopyrimidine derivatives from aliphatic fragmentswas carried out by frankland and kolbs in 1848. Since than a many distinct primarysynthetic methods has been devised. 1-5 Different methods reported are as under.1. The reaction of chalcones with thiourea in alkaline medium affordedcorresponding mercapto pyrimidine derivatives. 62. Liu-Fang Ming et al. 7 have synthesized mercapto pyrimidine by the reaction of1,3-diketones and thiourea.3. Mercapto pyrimidine can also be obtained by the condensation of β-dinitrileswith thiourea and guanidines. 84. 2-Mercaptopyrimidines can be synthesized by Atul Kumar et al.9 throughcondensation of thiourea and substituted â-ketoester in presence of Ziegler-Natta catalyst system under solvent free condition.5. Wei Yi Chen et al. 10 have been prepared dihydropyrimidin-2(1H)-ones (I) byusing HBF 4 as catalyst under solvent free condition.OOORHC H 3RO+N H 2R'NH 2SR'10 mol% HBF 4R=Aryl R’=CH 3 , OCH 2 CH 3Me(I)NHNHX6. By the controlled phase transfer catalysis conditions. 117. Wang Jinjun 12 have prepared some new benzo[c]pyrano[4,3-d]pyrimidinederivatives (II).Pyrimidine-2-thiones…

Studies on some compounds… 186ORH 2 N NH 2XMeOH, H +OO(II)R=Ph, 4-Cl-Ph, 3-OCH 3 -PhX=O, SMECHANISMONH 2RR'+AlkaliProton transferRR' H N S HNO2NH 2SOHRRR' RR'R'OH -HNNHN N -H + N N-H -SSHSHMechanism can be explained by the reaction between arylidene and thioureain which thiourea react with α, β-unsaturated system and electron transfer take placedue to the more electro negativity of oxygen atom than carbon atom. So, oxygen getnegative charge, it condense with amine of thiourea and remove water molecule, soformation of thiopyrimidine is one type of Cycloaddition process.THERAPEUTIC IMPORTANCEThiopyrimidines are excellent reservoir of bioactive substance. In the pastyears, the literature enriched with progressive findings about the synthesis andpharmacological action of thiopyrimidine derivatives. The important activities are asunder1. Antimicrobial. 13-142. Antitumor. 15-16HNXNHRPyrimidine-2-thiones…

Studies on some compounds… 1873. Anti-HIV. 17-184. Antiviral. 195. Anti-inflammatory and Analgesic.206. Antagonist. 217. Antihistaminic. 228. Antitubercular. 239. Antiherpesvirus. 24S. S. Sangapure et al. 25 have tested the antimicrobial activity of benzofuro[3,2- d]pyrimidine derivatives (I). El Sayed and co-workers 26 have synthesizedalkylated substituted mercapto pyrimidine derivatives (II) and studied their anticancerand antineoplastic activity. H. Y. Moustafa et al. 27 have reported some pyrimidinederivativesand studied their biological activities.SNHNNClO(I)NH 2H 3 CSN(II)CH 3N. V. Kaplina and co-workers 28 shows herpes inhibiting activity of somemercaptopyrimidine derivatives (III). Mai A. et al. 29have synthesized 5-alkyl-2-alkylamino-6-(2,6- difluorophenylalkyl)-3,4-dihydropyrimidin-4( 3H)-ones, a newseries of potent, broadspectrum non-nucleoside reverse transcriptase inhibitorsbelonging to the DABO family.R 2R 3R 1R 5R 4NSHN(III)Pyrimidine-2-thiones…

Studies on some compounds… 188Michael D. Varney and co-workers 30 have synthesized and evaluatedbiological activity of 5-thia-2,6-diamino-4(3H)-oxopyrimidines (IV) as potentinhibitors of glycinamide gibonucleotide transformylase with potent cell growthinhibition. Huang Y. L. et al. 31 have synthesized non-classical antifolates, 5-(Nphenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidinesand 2,4-diamino-6(5H)-oxopyrimidlines as antitumor activity.OArCOOHOS (CH 2 )nNHHNNH 2COOHN H 2N(IV)Viney Lather and co-workers 32 have been proposed to predict the anti-HIVactivity of dihydro(alkylthio)(naphthylmethyl)oxopyrimidines. These models arecapable of providing lead structures for development of potent but safe anti-HIVagents (V). H. S. Joshi et al. 33 have sythesized some new pyrimidines and reported asantitubercular and antimicrobial agents. Agarwal A. et al.34 have synthesized 2,4,6-trisubstituted pyrimidine derivatives as pregnancy interceptive agent. Sanmartin C. etal. 35 have prepared new symmetrical derivatives as cytotoxic agents and apoptosisinducers.OHNR 1XSNR(V)Marie Gompel and co-workers 36 have showed that meridianins inhibit variousprotein kinases such as cyclin-dependent kinases, glycogen synthase kinase-3, cyclicnucleotide-dependent kinases and casein kinase. Alistair H. et al.37 have synthesized anovel series of pyrimidine IKK-2 inhibitors which show excellent in vitro inhibitionof this enzyme and good selectivity over the IKK-1 isoform. L.G. Hammerland et al. 38have been studied structure-activity relationship of thiopyrimidines as mGluR5Pyrimidine-2-thiones…

Studies on some compounds… 189antagonists. R. H. Wiley et al. 39 have been synthesized some hydroxy-2-thiopyrimidine- 5-carboxaldehyde derivatives used in cancer chemotherapy. Patil L.R. et al. 40 have synthesized some new pyrimidines bearing paracetamol andimidazolyl moieties. Several thio analogues of pyrimidine were prepared based on theinitial activity screening of several analogues of these heterocycles againstMycobacterium tuberculosis (Mtb) by Ashish K. Pathak et al. 41 E. Ichikawa et al. 42have prepared nucleoside analogues of constitute an important class of biologicallyactive compounds, especially as antiviral and anticancer agents. Donn G. Wishka etal. 43 have been synthesized furo [2,3-c] pyridine pyrimidine thioether as potent HIV-1non-nucleoside reverse transcriptase inhibitors.Morever, H. S. Joshi and co-workers 44 have been synthesized some new seriesof thiopyrimidine bearing cinnoline nucleus and studied their antimicrobial againstdifferent microbes and antitubercular activity against MycobacteriumTuberculosis. R.A. Olmsted et al. 45 have been reported some thiopyrimidine derivatives as potent,HIV-1 non-nucleoside reverse transcriptase inhibitor.Shigeta S. et al 46 have been synthesized 5-alkyl-2-thiopyrimidine nucleosideanalogues and examined for antiviral activities against Herps Simplex virus (HSV),Varicella-Zoster virus (SZV) and Human Cytomegalo virus (HCMV). H. S. Joshi etal. 47 have sythesized some new pyrimidines (VI) and reported as antitubercular andantimicrobial agents.RNSHNH(VI)BrA.S.noravyan at el. 48 synthesized some thienopyrimidine derivatives andreported them as anticonvulsant agent. Hozein Z. et al 49 studied thienopyrimidinederivatives and evaluated for their antifungal and antibacterial activity. Moreover, M.et al. 50 assessed some thienopyrimidine derivatives (VII) as Antitumer andantibacterial agent.Pyrimidine-2-thiones…

Studies on some compounds… 190PhNN(VII)SHB.J.Ghiya et al. 51 demonstrated some thienopyrimidine derivatives andscreened for their anticancer, antitubercular and anti-HIV activities. Abou EI F. etal. 52 synthesized thienopyrimidine derivatives (VIII) which showed anticanceractivity. Erker T. et al. 53 have prepared thienopyrimidine which have been shown topossess muscle relaxant activity. Breozowskil Z. 54 found thienopyrimidine as antiHIV. Nakatsuka M.et al. 55 prepared thienopyrimidines active against inflammation.XHNSC H 3NNH(VIII)XLeone M. et al. 56 have studied some thienopyrimidines showing antibioticactivity. Takatani M et al. 57 and Scott K. et al. 58 have synthesized thienopyrimidinesassociated with marked hypolipemics and hypoglycemic, anticonvulsant activitiesrespectively. Schiafella F. et al.59 and Shafiee A. et al. 60 prepared thienopyrimidines &61evaluated for antifungal and anti-inflammatory activity respectively. Abdel R.showed antimicrobial activity and He Xiao-Shu 62 evaluated for dopamine receptoractivities.Sham M. Sondhi et al. 63 have synthesized pyrimidine derivatives (IX) by anefficient, one-pot reaction of functionalized amines with either 4-isothiocyanato-4-methyl-2-pentanone or 3-isothiocyanatobutanal.Pyrimidine-2-thiones…

Studies on some compounds… 191H 3 CH 3 CHNSNCH 3OSO(IX)SHNCH 3NCH 3H 3 CPratibha Sharma and co-workers 64 have investigated the insertion of dimethylvinylidene carbine into azo moiety was investigated in order to synthesize 4,6-dimethyl-5-[2-(2-methylprop-1-enyl)-1H-benzimidazol-1-yl]pyrimidine-2(5H)-thione(X) under kinetically controlled phase transfer catalysis conditions.SH 3 CNNNCH 3R(X)NCH 3H 3 CMethyl thiouracil (XI) 65 and iodo thiouracil (XII) 66 are well-known antithyroid drugs.IOHC H 3OHNNNNSH(XI)SH(XII)Pyrimidine-2-thiones…

Studies on some compounds… 192Thus, diverse biological activities have been encountered in compoundscontaining thiopyrimidine ring system. To further assess the potential of such type ofcompounds, studies of thiopyrimidine have been carried out as under.SECTION-4.1:-SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO - N – 3-(4-ARYL-2-MERCAPTO -1,4,-DIHYDROPYRIMIDINE- 6-YL)] BENZAMIDE.Pyrimidine-2-thiones…

Studies on some compounds… 193SECTION-4.1SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORO-N – 3-(4-ARYL-2-MERCAPTO-1,4,-DIHYDROPYRIMIDINE- 6-YL)] BENZAMIDE.Thiopyrimidines represent one of the most active classes of compoundspossessing a wide spectrum of biological activities, such as significant in vitro activityagainst DNA and RNA viruses including polio viruses, diuretic, antitubercularspermicidal etc. Thiopyrimidine derivatives of type -(IX) have been prepared by thereaction of the chalcones of type (I) with thiourea in presence of basic catalyst inethanol + DMF shown as under.ClClOONHRAlkaliThioureaClClRCompound-(IX)Type-(IX)HNONHNSThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (IX a-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (IXa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations.(Chapter-8).Pyrimidine-2-thiones…

Studies on some compounds… 194Reaction SchemeClClHNOOCH 3+HOAlkaliMethanolClClOORNHClAlkaliThioureaClRONHNNHSType- (IX)R=ArylPyrimidine-2-thiones…

Studies on some compounds… 195IR SPECTRAL STUDIES OF 2,3-DICHLORO-N –[3-{4-(p-METHOXYPHENYL)-2-MERCAPTO-1,4,-DIHYDROPYRIMIDINE-6-YL)]BENZAMIDE.C H 3OClClHNONNHSInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type VibrationFrequency in cm-1 Ref.modeObserved ReportedAlkane C-H str. (asym.) 2937 2975-2950 67-CH3 C-H str. (sym) 2837 2880-2860 "C-Hdef. (asym.) 1424 1470-1435 "C-H def.(sym.) 1336 1390-1370 "Aromatic C-H str. 3047 3090-3030 68C=C str. 1582 1540-1480 "C-H i.p. def. 1048 1125-1000 "C-H o.o.p. def. 811 835-810 "Moiety C-Cl (str.) 745 800-600 "Carboxamide -CONH- 1673 1700-1650 69Ether C-O-C (str..) 1213 1260-1200 70Thiopyrimidine C=S str 1582 1590-1550 "Amine -NH str 3219 3554-3350 "Vinyl CH=CH str 3021 3050-3000 "Pyrimidine-2-thiones…

Studies on some compounds… 196PMR SPECTRAL STUDIES OF 2,3-DICHLORO -N– [3-(p-METHOXYPHENYL)-2-MERCAPTO-1,4,-DIHYDROPYRIMIDINE 6-YL)] BENZAMIDE.C H 3OaClClihi'h'bcHNOdgNNHSfef'Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 3.76 1H singlet -OCH 32 7.21-7.25 2H doublet Ar-Hf, f’3 7.41-7.62 6H multiplet Ar-Ha,b,c,d,e,g4 7.65-7.78 2H doublet Ar-Hh, h’5 8.12-8.18 2H doublet Ar-Hi, i’6 8.20 1H Sing let -NH (pyrimi.)7 8.52 1H singlet -NH (-NHCO)Pyrimidine-2-thiones…

Studies on some compounds… 197MASS SPECTRAL STUDIES OF 2, 3-DICHLORO-N–3-[{4-(p-METHOXYPHENYL)-2-MERCAPTO-1,4,-DIHYDROPYRIMIDINE-6-YL}]BENZAMIDE.C H 3OClClHNONNHSm/z = 482.38Pyrimidine-2-thiones…

Studies on some compounds… 198MASS FRAGMENTATIONCl+0ClClClHNONHNSNH+0NSOHNm/z = 351+CH 20NHSClm/z = 452ClH 3 CO+0H 3 Cm/z = 188O+0ClClO+0HNONHNSm/z = 108CH 2NH 2HNm/z = 483 ( M. I. P.) = (B. P.)m/z = 307C H 3OC H 3OClClClClO+HNCH 0 NH 2 0O++0C H 2m/z = 135HNm/z = 426m/z = 291Pyrimidine-2-thiones…

Studies on some compounds… 199EXPERIMENTALSYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO-N – 3-(4-ARYL-2-MERCAPTO-1,4,-DIHYDROPYRIMIDINE- 6-YL)] BENZAMIDE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF N-(3-ACETYLPHENYL)-2,3-DICHLOROBENZAMIDE.Pls. refer Chapter-3, Section-3.1, page no.131[B] SYNTHESIS AND STRUCTURE ELUCIDATION OF 2, 3-DICHLORON-(3-SUBSTITUTED STYRYL CARBONYL) BENZAMIDE.Pls. refer Chapter-3, Section-3.1, page no.131[C] 2,3-DICHLORO-N-3-[(4-(P-METHOXYPHENYL)-2-MERCAPTO-1,4-DIHYDRO PYRIMIDINE-6-YL)] BENZAMIDE.A mixture of 2, 3-dichloro -N-(3-substituted styryl carbonyl) benzamide.(2.78gm, 0.01 mole) and thiourea (0.78gm, 0.01 mol) in ethanol (15 ml) was refluxed on awater bath in presence of alcoholic KOH for 12 hr. The solvent was distilled off andthe residue was neutralized with dilute HCl, the separated solid was filtered out andcrystallized from ethanol. Yield-58 %, m.p.-138 o C; [C 24 H 17 Cl 2 N 3 O 2 S; found: C,59.72, H, 3.52, N, 8.65, requires C, 59.76, H, 3.55, N, 8.71%].Similarly, other 2,3- dichloro-N-3-(4-aryl-2-mercapto-1,4- dihydropyrimidine-6-yl)] benzamide were prepared. The physical data are recorded in Table No:-9.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)Pyrimidine-2-thiones…

Studies on some compounds… 200[D] BIOLOGICAL EVALUATION 2,3-DICHLORO-N-3-(4-ARYL-2-MERCAPTO-1,4- DIHYDROPYRIMIDINE-6-YL)] BENZAMIDEAntimicrobial testing were carried out as described in Chapter-8. The zonesof inhibition of test solutions are recorded in Graphical Chart-9a, Table No. - 9a.Page No.-381,382. Result and discussion is given on page no.:- 383.Pyrimidine-2-thiones…

Studies on some compounds… 201● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Pyrimidine-2-thiones…

Studies on some compounds… 202REFERENCES: (Chapter-1: Ref. No.:- 1-70)1. N. S. Nandurkar, M. J. Bhanushali, M. D. Bhor, B. M. Bhanage;Jou. of Molecular Catalysis A: Chemical, 71, 14-17 (2007).2. F. Shirini, K. Marjani, H. T. Nahzomi;ARKIVOC, 51-57 (2007), ISSN 1424-6376.3. R. Gupta, S. Paul, R. Gupta;Jou. of Molecular Catalysis A: Chemical, 266, 50-54 (2007).4. M. M. Heravi, K. Bakhtiari, F. F. Bamoharram;Catalysis Communications, 7, 373-376 (2006).5. C. Liu, J. Wang, Y. Li;Jou.of Molecular Catalysis A: Chemical, 258, 367-370 (2006).6. Shaw and Nayler;J. Chem. Soc., 11, 69 (1959).7. Liu Fang-Ming, Yu Jain-Xin, Weng Mei, Liu Yu-Ting;Chem. Abstr., 117, 48600g (1992).8. Geodeng Xue Xiao Huaxue Xuebao; Bull Fac. Pharm., 19 (7), 1082-85(1998); Chem ., Abstr., 129, 161535a (1998).9. A. Kumar, R. A. Maurya; Jou.of Molecular Catalysis A: Chemical, 272, 53-56(2007).10. W. Chen, S. Qin, J. Jin; Catalysis Communications, 8, 123-126 (2007).11. P. Sharma, A. Kumar, M. sharma; J. Mol. Catal.-A. Chemical,237 (1-2), 191-198 (2005).12. W. Jinjun, Z. Jianmin, C. Bingzi; Huazue Tonghao., 10, 4-8-50 (1977).13. C. W. White, J. J. Traver So; J. Am. Chem. Soc., 78, 5294 (1956).14. H. A. Allimony, H. A. Saad, F. A. A. El-Mariah; Indian J. Chem., 38(B), 445-446 (1999).15. S. A. Swelam; Indian J. Heterocycl. Chem., 8 (2), 147-150 (1998), Chem.Abstr., 130, 237549 (1999).16. M. Mona, E. S. Megda, E. Obaid, M. A. Abdul-Rahman, A. Badria Farid;Alexandra J. Pharm. Sci., 12 (1), 39-44 (1998).17. D. Krzysztof, E. B. Pederson, C. N. Bielsen; J. Med. Chem., 41 (2), 191-198(1998).Pyrimidine-2-thiones…

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Studies on some compounds… 20436. M. Gompel, M. Leost, E. B. K. Joffe, L. Puricelli; Bioorg. Med. Chem. Lett.,14, 1703-1707 (2004).37. A. H. Bingham, R. J. Davenport, L. Gowers, L. Roland; Bioorg. Med. Chem.Lett., 14 (2), 409-12 (2004).38. L. G. Hammerland, M. Johansson, J. Malmstrom, J. P. Mattsson, A. B.Minidis, K. Nilsson, A. Peterson, D. Wensbo, A. Wallberg, K. Osterlund;Bioorg. Med. Chem. Lett., 16, 2467-2469 (2006).39. R. H. Wiley, K. F. Hussung, W. E. Hobbs, S. Huh; J. Med.Chem., 7, 358-359(1964).40. L. R. Patil, V. S. Ingle, S. P. Bondge, V. E. Bhingolikar, R. A. Mane; Ind. Jou.Chem., 40B, 131-134 (2001).41. A. K. Pathak, V. Pathak, L. E. Seitz, W. J. Suling, R. C. Reynolds; J. Med.Chem., 47, 273- 276 (2004).42. E. Ichikawa, K. Katoh; J. Synth. Org. Chem., Jpn., 59, 331-345 (2001).43. D. G. Wishka, D. R. Graber, E. P. Seest, L. A. Dolak, F. Han, W. Watt, J.Morris; J. Org. Chem., 63, 7851-7859 (1998).44. M. R. Patel, J. D. Akbari, D. H. Purohit, H. S. Joshi ; J. Ind.Chem. Soc., 84, 1-5 (2007).45. R. A. Olmsted, L. A. Kopta, D. G. Wishka, M. J. Murphy, S. T. Schlachter, R.A. Nugent, J. Morris ; Antiviral Res., 1998 Mar; 37: A54 (abstract no. 46).46. Shigeta S., Mori S., Watanabe F., Saneyoshi M.;Antivir. Chem. Chemother.,13(2), 67-82 (2002).47. K. S. Nimavat, K. H. Popat, S. L vasoya and H. S. Joshi; Indian J. Heterocycl.Chem., 12, 217(2003).48. A. S. Noravyan, Oranisyan A. Sr., Grigoryan G. O., Vartanyan S.; Chem.Abstr., 126, 70176f (1997).49. Hozein Zeinab A., Abdel Wahab A. A., Hassan K. M. M; Pharmazie, 52 (10),753-58 (1997); Chem. Abstr., 128, 22879g (1998).50. Mohran Mona A., Ei-Sherbeny Megade A., Abdul Rahman M. A.; AlexandriaJ. Pharma Sci., 12 (1), 39-44 (1998); Chem. Abstr., 129, 67756b (1998).51. B. J. Ghiya and Manoj Prabjavati; Indian J. Heterocyclic Chem., 7, 311-312(1992).52. Abou E-Fotooh, G. Hamman, Mohie A., Sharaf, Nagala A. Abd EI-Hafez;Indian J. Chem., 40 (B), 215-221 (2001).Pyrimidine-2-thiones…

Studies on some compounds… 20553. Erker Thomas, Heistracher Peter Lemtnens Gruber Rosu, Lexer Andreas,Schreder Maria Ausria; Austrian AT 403, 918 (1998); Chem. Abstr., 129,260468n (1998).54. Breozowski Zdzislaw; Pol. PL 173, 244; Chem. Abstr., 129, 148982z (1998).55. Nakatsuka Masahi, okada Shinichiro, Shimano Kazuori, Watanake Shoji; PCTInt. Appl. WO 98 , 42688 (1998); Chem Abstr., 129, 275918h (1998).56. Leono Mario, Zenoni Maurizio, Serra Maurizio, Fillippi Mauro; PCT Int,Appl. WO 99, 23, 082 (CIC07D277/16) (1999); Chem. Abstr., 131, 352134z(1999).57. Takatani Muneo, Sugiyama Yasuo, Kawamoto Tetsuji, Adachi Koji; PCT Int,Appl. WO 99, 20, 632 (CIC07D513/16) (1999); Chem. Abstr., 131, 311794w(1999).58. Scott Kenneth R., Lawa Mia L., Roberts Ralph R., Nicholson Jesse M. I.; PCTInt, Appl. WO 99, 21, 560 (CIA61K31/54) (1999); Chem. Abstr., 131,311808j (1999).59. Schiafella Fansto, Guarruci Alessia, Fringuella, Ranak, Pitzurra Lucia;Med.Chem Res., 1999; Chem . Abstr., 132, 78519g(2000).60. Shafiee A., Ahadzadeh B.;J.Sci. Islamic Repub. Iron 1998; Chem. Abstr., 132,12258c (2000).61. Abdel-Rahman T.M.; Boll. Chim, Farm (1998); Chem. Abstr., 132, 93276b(2000).62. He Xiao-Shu; U.S. US 6, 100, 255; Chem. Abstr., 133, 150581u (2000).63. Sham M. Sondhi, Rajendra N. Goyal and Ram Raghubir; Bioorganic &Medicinal Chemistry, 13(9), 3185-3195 (2005).64. A. S. Noranyan, Oranisyan A. Sr., Grigoryan G. O., Vartanyan S. et al.;ChemAbstr., 126, 70176f (1997).65. H. I. Wheeler and F. Mc Farland; American Chem. J., 42, 105 (1909).66. H. Barreu, I. Goodman and K. Dictormer; J. American Chem . Soc., 70, 1753(1948).67. V. M. Parikh; “Absorption spectroscopy of organic molecule” Additionweslay Pub. Co. London, 243, 258 (1978).68. A. R. Kartizky and R. Alan Jones;J. Chem. Soc., 294z (1960).69. F.V.Loffe;Pyrimidine-2-thiones…

Studies on some compounds… 206Khim. Geterokeiki Sodein, 6, 1089 (1968); Chem. Abstr., 70, 72338 (1986).70. D.L.Paria, G. M. Lampman and G. S. Kriz;Introduction to spectroscopy college publishing, Philadelphia, p-46 (1979).Pyrimidine-2-thiones…

CHAPTER - 5STUDIES ONCYANOPYRIDINES

Studies on some compounds… 207INTRODUCTIONPyridine is also called azabenzene and azine, is a heterocyclic aromatic tertiaryamine characterized by six-membered ring structure composed of five carbon atomsand a nitrogen atom which replaces one carbon-hydrogen unit in the benzene ring(C6H5N).Most of the derivatives are prepared by manipulation of pyridine and itssimple homologues in a manner similar to chemistry of the benzenoid chemistry.However, the simple pyridine compounds are prepared by the cyclization of aliphaticraw materials. Pyridine compounds are found in nature, for example nicotine fromtobacco, ricinine from castor bean, alkaloids such as coniine, piperine and nicotine.Some pyridine system is active in the metabolism in the body. Pyridine can be parentcomponent of targeted compounds such as insecticides, herbicides, medicines,vitamins, food flavoring, explosive and disinfectants.NCN(I)Among a wide range of pyridines, 3-cyanopyridines (I) acquired a specialattention due to their wide range of therapeutic activities. In our continuation of workin the chemistry of pyridine nucleus, we have undertaken the synthesis of some 3-cyanopyridine derivatives.SYNTHETIC ASPECTSMost of these derivatives are prepared by manipulation of pyridine and itssimple homologues in a manner similar to chemistry of the benzenoid chemistry.However the simple pyridine compounds are prepared by the Cyclization of aliphaticraw materials.Preparation of 3-cyanopyridines is available in the literature 1-5 with differentmethods.1. Samour and co-workers 6 have prepared substituted cyanopyridines (II) by thecondensation of chalcones with malononitrile in presence of ammonium acetate.Cyanopyridines…

Studies on some compounds… 208RR 1CNOR 1CH 3COONH 4CH 2(CN) 2(II)H 3 C N NH 22. Feng Shi and co-workers 7 have prepared 2-amino-3-cyanopyridine derivativeby the reaction of aromatic aldehyde, ketone, malononitrile and ammoniumacetate under microwave irradiation without solvent.3. Dao-Lin & Kimiaki 8 have prepared 2-methoxy-3-cyanopyridine derivatives(III) by the condensation of α, β-unsaturated ketone with malononitrile insodium methoxide.RR'NNRO+NNaOMeH 3 CO(III)NR'4. 2-Trihalomethyl 5-cyanopyridine (IV) have been synthesized by Jason WBCooke. 9EtOOCF 2 XNC+TolueneNH 4OACDMFNMe 2NCN(IV)CF 2 X5. Sakuri and Midorikaw 10,11 have reported that malononitrile reacts with α, β-unsaturated ketones to give 2-amino-3-cyano-4,6-disubstituted pyridines.6. By cyclocondensation of cyanoacetamide with ethyl acetoacetate in presenceof base. 127. By the reaction of 3-substituted phenyl pyrazolone derivatives withmalononitrile. 138. By the reaction of arylidene malononitrile with lithium isopropyl amide indimethyl formamide-dichloromethane. 14,159. By the vapour phase air oxidation of nicotine over V 2 O 5 16 or alkenyl17substituted pyridines in presence of ammonia and V-Mo-P catalyat.Cyanopyridines…

Studies on some compounds… 20910. By the reaction of pyridine-3-carboxylic acid with ammonia in the presence ofdehydrating catalyst at 275°C to 450 °C. 18,1911. By heating potassium salt of 3-pyridine-sulphonic acid with sodium cyanide at350°C to 400 °C. 2012. By heating pyridine-3-carboxamide in the presence of TiCl4 and a basetrimethyl amine at 0 °C. 2113. By the reaction of an alkali cyanide with 3-pyridine sulphonate 22 or 3-bromopyridine. 23MECHANISMThe reaction proceeds through conjugate addition of active methylenecompounds to the, β unsaturated system as shown below.ROR'+CNCNR R'CH 3COONH 4NHNC CNRRCN-2HR' N NH 2R'NHCNNHRNCCNNH 2R'THERAPEUTIC IMPORTANCEMuch research has been carried out with an aim to finding therapeutic valuesof pyridine skeleton since their discovery. The pyridine derivatives are reported toexhibit a wide variety of biological activities.1. Antifungal. 242. Antiepileptic. 253. Antibacterial. 264. Anticonvulsant. 275. Antitubercular. 286. Analgesic. 297. Insecticidal. 30Cyanopyridines…

Studies on some compounds… 2108. Antisoriasis. 319. Antihypertensive. 3210. Bacteriostatic activity. 33-3511. Antiphlogistic activity. 3612. Anti-inflammatory activity.3713. Antiallergic activity. 38Streightoff A. 39 and Seydel J. 40 have studied the bacteriostatic effect of some41substituted 3-cyanopyridines. J. A. Van Allan et al.heterocyclic 3-cyanopyridine. (I)have prepared fusedC 6H 5NS(I)NNH 2NBarton et al. 42cyanopyridines. J. J. Baldwin 43-45have reported fungicidal and insecticidal properties ofhypertensive activity. V. Scott and E. Joseph 46,47have prepared cyanopyridines exhibiting antihave prepared 2-amino-3-cyanopyridine derivatives which were found to be useful as antipsoriasis. Miertus et48al. synthesized 2-formyl 3-cyanopyridine thiosemicarbazone as a carcinostatic agent.S. S. Verma et al. 49 and M. D. Ankhiwala 50 have synthesized 2-amino-3-cyano-2,6-disubstituted pyridines and studied their biological activities. F. Manna et. al.51 haveprepared 3-cyanopyridine derivatives as anti-inflammatory, analgesic and antipyreticagents. Gadaginamath and co-workers 52derivatives (II) and documented their biological activities.have synthesized various cyanopyridineOCH 3H 3 CON H 2NNCH 3NC(II)RCyanopyridines…

Studies on some compounds… 21153The insecticidal activity of cyanopyridines has been screened by Y. Sasakiand coworkers. Pankaj Patel & co-workers 54 have synthesized cyanopyridines andevaluated their biological activity. Umed Ten et al.55 have prepared cyanopyridines asagro fungicides.The oxide activator bleaching activity of cyanopyridine has been proved byRees W. M. 56 Oshida M. 57 prepared cyanopyridine derivatives which inhibitedcerebral edema and delayed neuron death. Hence, they are useful as cerebral edemainhibitors or cerebrovascular disorder remedies. S. Guru et al. 58 have synthesizedvarious cyanopyridine derivatives (III) and documented their multiple biologicalactivities.RONN(III)NH 2R=ArylSome other new cyanopyridine derivatives are reported for their cholinesteraseinhibitors, 59 antihistaminic and adrenergic, 60 herbicidal, 61 anti-inflammatory 62 &insecticidal 63 activities. H. Yoshida et. al. 64 have studied the antihistaminic &antiallergic activity of 3-cyanopyridine derivatives. John A. Tucker et al.65 havesynthesized novel piperazinyl oxazolidinone containing cyanopyridine (IV) as anantibacterial agents.NNNNOF(IV)NONHAcCyanopyridines…

Studies on some compounds… 212El-Nabawia et al. 66 have prepared new 2-amino-3-cyano pyridine derivatives(V) and studied their antimicrobial activity.OCH 3N H 2NNCH 3NC(V)RAbdallah N. et al. 67 have synthesized cyanopyridine derivatives which showsanalgesic and anti-inflammatory activity. Adriano Atonso et al.68 have found thatcyanopyridines are Farnesyl protein transferase inhibitors. Aivars Kruaze et. al.69 havesynthesized 3-cyanopyridine derivatives & shown their neurotropic activity. Abu andco-workers 70 have described novel fused cyanopyridines (VI) for the treatment ofsystemic fungal infection.CH 3NH 2CNNCNN H 2NS(VI)Rajeev Doshi and co-workers 71 have described some novel cyanopyridines asa new class of potential antitubercular agents.Abd El-Galil and co-workers 72 have prepared 3-cyanopyridines (VII) andstudied their pharmacological activity. Hammung E. and Abou and co-workers 73 havestudied the anticancer and anti-HIV activity of 3-cyanopyridines.ArArNCCNNH 2 N NN NH 2(VII)Cyanopyridines…

Studies on some compounds… 213Edwin B. Villhauer and co-worker 74have synthesized the series ofcyanopyridines as a DPP-IV inhibitor. One compound (VIII) is profiled as a potent,selective and short acting DPP-IV inhibitor that has excellent oral bioavailability andpotent antihyperglycemic activity. S. V. Roman et. al.75 have investigated 2-amino-3-cyanopyridine derivatives and reported their biological activity.NCOCNNNHNHN(VIII)El-Tawell and co-workers 76 have described cyanopyridine derivatives (IX) andshowed their significant biological activity.NCNH 2N(IX)OPyachenko U. D. and co-workers 77 have shown some cyanopyridines (X)useful in treatment of retroviral disease. Cyanopyridines have been screened by A. V.Dobaria et. al. 78 and showed their significant biological activity.CNSeNCNH 2N(X)Hussain et al. 79 have synthesized cyanopyridines as antimicrobial agent. WuWenxue et al. 80 have synthesized cyanopyridines as histamine H3 antagonists. HaradaCyanopyridines…

Studies on some compounds… 214Hironori et al. 81 have prepared cyanopyridines and screened for their largeconductance calcium activated potassium channel opener activity. Marco J. L. et al 82have synthesized cyanopyridines of acetyl cholinesterase inhibitors.Rosentreter Ulrich et al 83 have synthesized a new cyanopyridine (XI) asreceptor agonists in the treatment of cardiac disease, cancer, inflammation andneurodegenerative disease. Moustafa M. A. et al. 84 have prepared cyanopyridinederivatives and evaluated for their antibacterial activity.H 2 NCNNR 2 CH 2 SCNO(CH 2 )n OR 1(XI)Fatma Goda & co-workers 85studied their antimicrobial activity.have synthesized cyanopyridines (XII) andArCNArN(XII)O CH 3Ketan Hirpara & co-workers 86 have discovered cyanopyridines asantitubercular agents (XIII). Eduardo H.S. Sousa et al 87 have synthesizedcyanopyridine derivatives as an antituberculosis.NSRN(XIII)NNH 2NHenryk foks et al. 88 investigated new 3-cyanopyridine derivatives showing anantibacterial activity. Abdel-Galil E. Amr and Mohamed M. Abdulla89 haveCyanopyridines…

Studies on some compounds… 215synthesized pyridine derivative (XIV) fused with steroidal structure. Initially theacute toxicity of the compounds was essayed via the determination of their LD50.ArH 3 CCH 3CH 3NC(XIV)NO CH 3Gary T. Wang and co-worker 90 have synthesized 2’-trifluoromethylbiphenylsubstituted 2-amino-nicotinonitrile (XV) as inhibitors of farnesyl transferase.CF 3NNCCNR 1NR 2NOH 3 CN(XV)V. H. Shah et.al. 91 have synthesized 2-amino-3-cyano-4-(m-phenoxy phenyl) -6-aryl-pyridines and evaluated for antimicrobial activity (XVI).OCN(XVI)RNNH 2Cyanopyridines…

Studies on some compounds… 216In light of wide varieties of biological activities exhibited by cyanopyridine, itappeared of interest to synthesize cyanopyridine derivatives in order to achievingcompounds having better therapeutic activity described as underSECTION:-5.1: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO-N-[3-(2-AMINO,4-ARYL-3-CYANO PYRIDINE-6-YL)] BENZAMIDE.Cyanopyridines…

Studies on some compounds… 217SECTION-5.1SYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO- N- [3-(2- AMINO, 4-ARYL-3-CYANO PYRIDINE-6-YL)] BENZAMIDE.The pyridine nucleus is found in a large number of commonly used drugswhich have diverse pharmacological activities. To achieving better drug potencycyanopyridine derivatives of type-(X) have been prepared by the condensation ofchalcones (compound-IV) and malononitrile as shown below.ClClOONHRCH 2(CN) 2CH 3COONH 4ClCompound-(X)Type-(X)R=ArylClHNORNNH 2NThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (Xa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (Xa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloremphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations,Selected compounds have been also screened for their antitubercular activity(chapter-8).Cyanopyridines…

Studies on some compounds… 218Reaction SchemeClOClNHO+OHCH 3NaOHEthanolClOClNHORCH 2(CN) 2 CH 3COONH 4ClClHNORNNH 2NType- (X)R=ArylCyanopyridines…

Studies on some compounds… 219IR SPECTRAL STUDIES OF 2,3-DICHLORO -N- [3-2-AMINO-4-(p-METHOXY PHENYL) -3-CYANO PYRIDINE-6- YL)] BENZAMIDE.H 3 COClClOCNHNN NH 2Instrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc.)Type VibrationFrequency in cm-1 Ref.modeObserved ReportedAlkane C-H str. (asym.) 2928 2975-2950 92-CH3 C-H str. (sym) 2833 2880-2860 "C-Hdef. (asym.) 1444 1470-1435 "C-H def.(sym.) 1353 1390-1370 "Aromatic C-H str. 3020 3090-3030 93C=C str. 1524 1540-1480 "C-H i.p. def. 1032 1125-1000 "C-H o.o.p. def. 850 835-810 "Moiety C-Cl str. 778 800-600 94Carboxamide CONH 1610 1680-1630 95pyridine C≡N str. 2220 2240-2220 "Nitrile C=N str. 1582 1640-1500 "C-N str. 1136 1220-1020 "Ether C-O-C 1221 1200-1260 "Cyanopyridines…

Studies on some compounds… 220PMR SPECTRAL STUDIES OF 2,3-DICHLORO -N- [3-(2-AMINO-4-(p-METHOXY PHENYL) -3-CYANO PYRIDINE-6- YL)] BENZAMIDE.H 3 COClii'aClhh'bcHNOdgCNN NH 2fef'Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 3.88 1H singlet -OCH 32 6.82 2H singlet (Broad) -NH 23 7.11-7.22 2H doublet Ar-Hf, f’4 7.44-7.96 8H multiplet Ar-Ha,b,c,d,e,g5 7.98 4H double doublet Ar-Hh, h’,i, i’8.38 1H singlet -NH (-NHCO)Cyanopyridines…

Studies on some compounds… 221MASS SPECTRAL STUDIES OF 2,3-DICHLORO -N- [3-2-AMINO-4-(p-METHOXYPHENYL) -3-CYANO PYRIDINE-6- YL)] BENZAMIDE.H 3NH 2COClClOCNHNNm/z = 489.35Cyanopyridines…

Studies on some compounds… 222MASS FRAGMENTATIONClH 3 COOH+0ClHNO+0N NH 2COH 3m/z =159m/z =94H 3 CO+0ClClm/z =463N+m/z = 108HNON+0H 3 COCOClClm/z = 174m/z =291O +ClClHNONNH 2N+0m/z =489 ( M. I. P.) = (B. P.)ClClH 3m/z = 413+0ONHNH 2N H 2+N 0CH 2+0ClClm/z =118m/z =120NH 2HNOCH 2NH 2+0ClClm/z =308m/z =191ONH 2+0Cyanopyridines…

Studies on some compounds… 223EXPERIMENTALSYNTHESIS AND STRUCTURE ELUCIDATION OF 2,3-DICHLORO- N- [3-(2- AMINO, 4-ARYL-3-CYANO PYRIDINE-6YL)] BENZAMIDE.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF N-(3-ACETYLPHENYL)-2,3-DICHLOROBENZAMIDE.Pls. refer Chapter-3, Section 3.1, Page No.131[B]PREPARATION OF 2,3- DICHLORO -N- (3-SUBSTITUTED STYRYLCARBONYL) BENZAMIDE.Pls. refer Chapter-3, Section 3.1, Page No.131[C] PREPARATION OF 2,3-DICHLORO -N- [3-(2-AMINO, 4-(p-METHOXY PHENYL )-3-CYANO PYRIDINE-6YL)] BENZAMIDE.A mixture of 2,3- dichloro -N- [3-(4-methoxy styryl carbonyl)] benzamide,(4.5 gm 0.01mole), malononitrile (1.5 gm, 0.01mole) and ammonium acetate (9 gm0.12 mole) dissolved in absolute alcohol (50ml) were heated under reflux for 12 hrs.,cooled and poured in to crushed ice. The product was separated, filtered andcrystallized from dioxane. Yield-62%, m.p.-235 . C; [C 26 H 18 Cl 2 N 4 O 2 ; required: C,63.81; H, 3.71; N, 11.45 %; found: C, 63.75; H, 3.66; N, 11.42%].Similarly, other cyanopyridines have been prepared by the same method. Thephysical data are recorded in Table No.-10.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)[D] BIOLOGICAL EVALUATION OF 2, 3-DICHLORO- N- [3-(2- AMINO,4-(ARYL)-3-CYANOPYRIDINE-6-YL)] BENZAMIDE.Antimicrobial testing were carried out as described in Chapter-8. The zonesof inhibition of test solutions are recorded in Graphical Chart-10a, Table-10a. PageNo.-384,385.Result and discussion is given on page no.:-386.Cyanopyridines…

Studies on some compounds… 224● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Cyanopyridines…

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Studies on some compounds… 229PCT Int. Appl. WO 98, 21, 199 (1998); Chem. Abstr., 129, 27898t (1998).62. Mama Fedele, Franco C., Adriana B., Bruna B., Walter F., Amelia F.;Eur. J. Med. Chem., 34(3), 245-254 (1999); Chem. Abstr., 131, 352178s(1999).63. Hussain K. M., Ruzial H., Ahmed S., Nizamuddin;Ind. J. Chem.., 37B(10), 1069-1074 (1998); Chem. Abstr., (131), 237504h(1999).64. Yoshida Hirashi, Kiyoshi O., Yasujuki Y., Kensaku F.;JP 10, 120, 677 (1998); Chem. Abstr., 129, 16062q (1998).65. John A. Tucker, Debra A. Allwine, Kevin C. Grega, Michael R. Barbachyn,Jennifer L.J. Med. Chem., 41, 3727-3735 (1998).66. El-Nabawia El-Said Goda, Alexandria F.;Chem. Abstr., 132, 151650g (2000).67. Abdallah Nevine A., Zakimagdi E. A.;Chem. Abstr., 132, 137287n (2000).68. Atonso Adriano, Kelly J. M. Weinstein J. Wolin R. L., Rosenblum S. B.;PCT Int. Appl. WO 98 59,950 (Cl. C07D (401/04); Chem. Abstr., 130, 81408s(1999).69. Aivars Kruaze, Gunars Duburs, et. al.;Eur. J. Med. Chem., 34(4), 301-310 (1999).70. Abu-Shana B, Fathi A, Satyed Ahmed Z., El-Gaby;Al-Azhar Bulletin of Sci, 10(1), 63-70 (Eng.) (1999); Chem. Abstr., 136,85768f (2002).71. Rajeev Doshi, Preeti Kagathara, Parekh H. H.,Ind. J. of Chem., 38(B), 348-52 (1999).72. Abd El-Galil and E. Amr;Indian J. Heterocyclic Chem., 10, 49-54 (2000).73. Hammung E. G., Abou El-Hafezu Najia, Abd A., Midarus Wandall;Chem. Sci., 25, 455-457 (2000).74. Edwin B. Villhauer, John A. Brinkman, Goli B. Naderi, Beth E. Dunning,Bonnie L.;J. Med. Chem. 45, 2362-2365 (2002).75. Roman S. V., Dyachenko V. D.;Cyanopyridines…

Studies on some compounds… 230Chem. Abstr., 136, 8670x (2002).76. El-Tawell F. M. A., Soton M. A.;Chem. Abstr., 137, 63154w (2002).77. Pyachenko U. D., Roman S. V. ;Chem. Abstr., 136(21), 325448x (2002).78. Dobaria A. V., Patel J. R., Parekh H. H.;J. Indian Chem. soc., 79, 772-773 (2002).79. Hussain M. M. M. and M. K. Mona;Indian J. Chem., 42(B), 2136-2141 (2003).80. Wu Wenxue, Liao Honghiclo, Tsai D. J. S.;PCT Int. Appl. WO 03 33488 (2003) (Cl. C07D 401-06); Chem. Abstr., 138,337996 (2003).81. Harada Hironori, Takuwa Tomofumi, Okazaki Toshio, Hirano Yusuke;Jpn. Kokai Tokkyo Koho JP., 03 2,06,230 (2003). (Cl. A61K 031-4418),Chem. Abstr., 139, 41663 (2003).82. Marco J. L., Carreiras M.C.;Mini Rev Med Chem. 3(6), 518-24 (2003).83. Rosentreter Ulrich, Kraemer Thomas et al.;Ger. Otten. DE 10, 238, 113 (Cl,CO 7D213/60) (2003).84. Moustafa M. A., Nasr M. N., Gineinah M. M., Bayoumi W. A.,Arch Pharm (Weinheim). 337(3), 164-70 (2004).85. Goda Fatma E., Alaa A. M. Abdel-Aziz & Omer A. Altef.;Bioorg & Med. Chem., 12(8), 1848-1852 (2004).86. Ketan Hirpara, Satyan Patel, Asutosh Joshi, and Hansa Parekh;Ind. J. of Hetero. Chem., 13, 221-224 (2004).87. Eduardo H., Sousa S., Daniel L. Pontes, Izaura C., Diógenes N., Luiz G.,Lopes F.,Journal of Inorganic Biochemistry, 368-375 (2005).88. Henryk Foks, Danuta Pancechowska-Ksepko, Anna K’dzia, Zofia Zwolska.;Il Farmaco, 60(6-7), 513-517 (2005).89 Abdel-Galil E. Amr and Mohamed M. Abdulla;Bioorganic & Medicinal Chemistry, 14(13), 4341-4352 (2006).90. Gary T. Wang, Xilu Wang, Weibo Wang, Lisa A. Hasvold, Gerry Sullivan.;Bioorganic & Medicinal Chemistry lett. 15(1), 153-158 (2005).Cyanopyridines…

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CHAPTER - 6STUDIES ONDIHYDROPYRIMIDINES

Studies on some compounds… 232INTRODUCTIONDihydropyrimidine is the most important member in all the diazines. Thechemistry of pyrimidines and their derivatives has been studied for over a century dueto the association of these systems with a variety of biological properties. In 1893, thesynthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) viamulticomponent reactions (MCRs) of an aromatic aldehyde, urea and ethylacetoacetate was reported for the first time by P. Biginelli. 1 This efficient approach topartly reduced pyrimidines was largely ignored in the following decades andtherefore, the pharmacological properties of this interesting heterocyclic scaffoldremained unexplored. Since the early 1980s, however, interest in dihydropyrimidonesof type (I) has increased significantly 2 . This was originally due to the apparentstructural similarity of DHPMs to the well known dihydropyridine calcium channelmodulators of the Hantzsch type 3 (II). It was soon established that DHPMs exhibit asimilar pharmacological profile to DHP calcium channel modulators of the nifedipinetype and various activities have been observed in this area from 1980s to 1990s. 4-5Recently, the interest in the synthesis of these derivatives has been increasedtremendously because they exhibit promising activities as calcium channelmodulators, antihypertensive agents, α-1a receptor antagonists and neuropeptide Y(NPY) antagonists 6,7 8in anticancer drug capability of inhibiting Kinesinmotor protein.Recently, interest has shifted from DHPM calcium channel modulators to otherbiologically active DHPM derivatives, e.g. α1a adrenoceptor selective antagonistswhich are useful for the treatment of benign prostatic hyperplasia. 9Again, thepharmacological activity in the area of α-1a adrenergic antagonists is based onactivity found earlier in the DHP series of compounds. However,dihydropyrimidinones of type (I) represent much more than just being aza analogs ofdihydropyridines of the Hantzsch type (II).ArArER 6NHDHPM(I)NHXER 6NHDHP(II)ER 2E= ester, amide, acylR 2,R 6= alkylX = O, SAr = Substituted arylDihydropyrimidines…

Studies on some compounds… 233The synthetic strategies for the dihydropyrimidine nucleus involve one-pot tomulti step approaches. The production of dihydropyrimidinones via the wellestablished Biginelli reaction certainly ranks as one of the most recognize and oftenused MCRs for the generation of novel pyrimidine scaffolds.10-13 The use ofmulticomponent reactions (MCRs) to generate interesting and novel drug likescaffolds is replete in the recent chemical literature. 14-16 Multicomponent reactions(MCRs) are of increasing importance in organic and medicinal chemistry.17-22 When a20,21premium is put on speed, diversity and efficiency in the drug discovery process,MCR strategies offer significant advantages over conventional linear typesynthesis. 17-22SYNTHETIC ASPECTSLiterature survey reveals that several publications and patents have describedthe synthesis of dihydropyrimidines as under.1. Over 100 years ago, 4-Aryl-3,4-dihydropyrimidine-2(1H)-ones of type(I)DHPMs) was reported for the first time. In 1893. The Italian chemist PietroBiginelli discovered a multicomponent reaction of aldehydes, urea or thioureaand β-dicarbonyl compounds that produced these multifunctionalizeddihydropyrimidones 1 in a simple one pot process.RH OO+O H 2 NR 1NH 2OH + / EthanolR 1ORNH(I)NHO2. DHPM-2(1H)-ones were prepared in high yield by Biginelli condensation ofan aldehyde, dicarbonyl compound and urea in ethanol using Mn(OAc)3 as acatalyst 23 .3. Substituted 3,4-DHPM-2(1H)-ones were prepared in high yield by Biginellicondensation of an aldehyde, dicarbonyl compound and urea in ethanol usingCoCl2.6H2O catalyst 24 .Dihydropyrimidines…

Studies on some compounds… 2344. A simple effective synthesis of DHPM-2-(1H)-one derivatives, using boricacid as a catalyst from an aldehyde 1,3-dicarbonyl compound and urea inglacial acetic acid is described by Tu Shujang et al. 25 Compared with theclassical Biginelli reaction conditions, this new method has the advantage ofexcellent yield 86-97% and the short reaction time (0.5-2hr).5. Ethyl-2-(methylthio)-6-oxo-1,6-dihydro-pyrimidine-5-carboxylate (II) hasbeen investigated by M.A.Hassan et al. 26 by the reaction of 5-carboethoxy-2-thiouracil, methyl iodide with the use of tetra butyl ammonium bromide (PTC)as a catalyst with continuous efficient stirring for 4-6 hrs at 70˚C.OOOONO CH 3TBAB, CH 3 INO CH 3HSNStirring 4-6 hH 3 CSN(II)BUILDING BLOCKS AND CATALYTIC DIVERSITY:As the earlier examples of this cyclocondensation process typically involvedβ- ketoester, aromatic aldehyde and urea, the scope of this heterocyclic synthesis hasnow been extended considerably by variation of all three building blocks, allowing10, 12access to a large number of multifunctionalized pyrimidine derivatives.Diversity of aldehyde building blocks:Out of the three building blocks in the Biginelli reaction it is the aldehydecomponent, which can be varied to the largest extent. In general, the reaction worksbest with aromatic aldehydes. These can be substituted in the o, m or p position witheither electron-withdrawing or donating groups. Aliphatic aldehydes typically provideonly moderate yields in the Biginelli reaction unless special reaction conditions areemployed, i.e. Lewis acid catalysts/solvent free methods or using the aldehydes inprotected form 27 . In such transformations, DHPMs having a sugar-like moiety atposition 4-(C-nucleoside analogs) (III), (IV) are obtained 28,29 . In a few cases,30bisaldehydes have been used as synthon Biginelli reactions.Dihydropyrimidines…

Studies on some compounds… 235HOHOOHOHHOEtOOCHHHOHNHOHOHOEtOOC H HNHHHONH(III)OH 3 CNH(IV)OSome of the aldehyde and protected aldehyde building blocks used in theBiginelli reaction is as under.OMeNO 2MeOOCH 3CH 3NHBrCHOCHOCH 3CHOCH 3OHCOHCOBnCHOCHOBnOOBnClClO CH 3BnOOHCHODiversity of CH- acidic carbonyl building blocks :Traditionally, simple alkyl acetoacetates are employed as CH-acidic carbonylbuilding blocks but other types of 3-oxoalkanoic esters or thioesters can also be usedsuccessfully 10 .Dihydropyrimidines…

Studies on some compounds… 236Li-Wen Xu, et. al. 31 described a synthesis of 5-unsubstituted 3,4-dihydropyrimidine-2(1H)-one (V),(VI) using acetophenone as a CH-acidic carbonyland aromaticaldehyde and urea in the presence of FeCl3–TMSCl as catalyst.H ONH +CH 3 NH+2N OOH N O2NHNHO(V)(VI)4-Hydroxycoumarin on reaction with aldehydes in the presence ofurea/thiourea using solid inorganic support under microwave irradiation (MWI)afforded 4-substituted benzopyrono [4,3-d]- pyrimidine (VII) derivatives in a fewseconds. 32ROOO+N H 2ONH 2XMWIAcidic solid supportOORNH(VII)NHXAhmad Shaabani et. al. 33 synthesized Spiro-fused heterocycles in good to highyields by a pseudo four-component reaction of an aldehyde, urea and a cyclic β-diester or α,β-diamide such as Meldrums acid or barbituric acid derivatives usingmicrowave irradiation under solvent-free conditions.(VIII)Dihydropyrimidines…

Studies on some compounds… 237zx xOO+H 2 N NH 2OCHORMWI4 minRxOHNX = O, Z= CMe 2zOxONHX= NH, Z= COR(VIII)are as under.Different CH-Acidic carbonyl building blocks used in the Biginelli reactionEtOOPhHNOEtSOO 2 NEtOMeOMeOMeOOOOClOMeOOMeOMeOOMeDiversity of catalyst in the Biginelli synthesis :The Biginelli condensation is strongly dependent on the amount of acidiccatalyst present in the reaction medium. Traditionally, strong Bronsted acids such ashydrochloric or sulphuric acid have been employed but nowadays the use of Lewisacids such asBF3-OEt 2 and CuCl 34 , FeCl 3 35 or Yb(OTf) 3 36 is preferred. In fact aplethora of different methods and conditions for synthesizing DHPMs according to37the Biginelli principle is known today, ranging from mg to kg scale.Youquan Deng et, al. 38 described a synthesis of 3,4-Dihydropyrimidine-2(1H)-ones (IX) in high yields by one-pot three-component Biginelli condensation in thepresence of ionic liquids such as 1-n-butyl-3-methylimidazolium tetrafluoroborateDihydropyrimidines…

Studies on some compounds… 238(BMImBF4) or hexafluorophosphate (BMImPF6) as catalysts under solvent free andneutral conditions at room temperature.OROREtOC H 3O+ON H 2NH2Xionic liquidEtOH 3 CNHNHXX= O, S(IX)Silica gel supported sodium bisulfite catalyzes efficiently the three componentcondensation reaction of aldehyde, β-ketoester and urea in refluxing acetonitrile toafford the corresponding dihydropyrimidinones. 39 (X)OROREtOC H 3O+ON H 2NH2XSiO 2 - NaHSO 4CH 3 CN, RefluxEtOC H 3NHNHXX= O, S(X)A simple and green chemistry procedure for the synthesis ofdihydropyrimidi nones (XI) using heteropoly acid mediated cyclocondensationreaction is as under. 40OROREtOC H 3O+ON H 2NH2XHPAEtOC H 3NHNHXX= O, S(XI)Diversity of Urea-type building blocks in the Biginelli synthesis:The urea is the component in the Biginelli reaction that faces the mostrestrictions in terms of allowed structural diversity 10 . Therefore, most of the publishedDihydropyrimidines…

Studies on some compounds… 239examples involve urea itself as building block. However, simple monosubstitutedalkyl ureas generally react equally well, in a regiospecific manner, to provide goodyields of N1- substituted DHPMs.Thiourea and substituted thiourea follow the same general rules as ureas,although longer reaction times are required to achieve good conversions. Yields arecomparatively lower than the corresponding urea derivatives.In some instances it is also possible to react protected urea or thiourea(isourea) or guanidine of type (XII) under weak basic conditions with the aldehydeand CH-acidic carbonyl component (or with a precondensed Knoevenagel type enone)to yield the corresponding protected DHPM 41,42 . This later method, usingprecondensed enones of type (XIII) has been frequently referred to as the “Atwalmodification” of the Biginelli reaction. 10,12,43Comparison and diversify analysis of the Biginelli and Atwaldihydropyrimidines (XIV) synthesis is as under.NH 2R 4NHEO R 1acidR 6 OXER 4R 6R 1NNHXR 4ObasedeprotectionNH 2ER 4N H 2baseXR(XII)ER 4NR 6O(XIII)R 6R 1 , R 4 , R 6 = H, alkyl, (het) arylNH(XIV)XRX= O, S, NRE= ester, amide, acyl, nitroDihydropyrimidines…

Studies on some compounds… 240REACTION MECHANISMSince the 1930s several mechanistic pathways have been proposed for theBiginelli reaction. In 1933, Folkers and Johnson reported that one of threeintermediates (XV), (XVI) was likely present in this reaction 44 . These includedbisureide (XV) which was formed by a condensation reaction between thearylaldehyde and the urea followed by subsequent attack of the resultant imine withanother equivalent of urea. Also, (XV) urido ethyl acrylate (XVI) arose from acondensation reaction between of the β-ketoester and urea finally, the reaction of theβ-ketoester and the aldehyde delivered the aldol adduct (XVII).HNONH 2EtOOCOONH 2OPhNHC H 3NC H 3OEtN H 2OH(XV) (XVI) (XVII)PhFourty years after the initial proposal, Sweet and Fissekis proposed a moredetailed pathway involving a carbenium ion species 45 . According to these authors thefirst step involved an aldol condensation between ethyl acetoacetate (XVIII) andbenzaldehyde (XIX) to deliver the aldol adduct (XX). Subsequent dehydration of(XX) furnished the key carbenium ion (XXI) which was in equilibrium with enone(XII). Nucleophilic attack of (XXI) by urea then delivered ureide (XXIII).Intramolecular cyclisation produced a hemiaminal which underwent dehydration toafford dihyropyrimidinone (XXIV). These authors demonstrated that the carbeniumspecies was viable through synthesis. After enone (XXII) was synthesized, it wasallowed to react with N-methyl urea to deliver the mono-N-methylated derivative ofDHPM (XXIV).Dihydropyrimidines…

Studies on some compounds… 241O OH 3 COEt+PhOHEtOOCPhOH(XVIII) (XIX) H 3 C O (XX)EtOOCPhONHNH 2H + +OH 2 N NH 2EtOOCH +-H 2 OPhH 3 CO(XXIII)(XXI)H 3 CO-H 2 OEtOOCPhNEtOOCPhC H 3NH(XXIV)OH 3 C(XXII)OThe mechanism was then reexamined 25 years later in 1997 by Kappe 46 .Kappe used 1 H and 13 CNMR spectroscopy to support the argument that the keyintermediate in the Biginelli reaction was iminium species (XXVI).In the event,benzaldehyde reacted with urea to form an intermediat "hamiaminal"(XXV) whichsubsequently dehydrated to deliver (XXVI).Iminium cation (XXVI) then reacted with(XVIII) to give (XXIII), which underwent facile cyclodehydration to give(XXIV).Kappe also noted that in the absence of (XVIII), bisureide (XV) wasafforded as a consequence of neucliophilic attack of (XXVI) by urea. This discoveryconfirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal form25 years earlier by Sweet and Fissekis, kappe saw no evidence by 1H and 13C NMRspectroscopy that a carbenium ion was a required species in the Biginelli reaction.When benzaldehyde (XIX) and ethyl acetoacetate (XVIII) were mixed underBiginelli conditions the requisite aldol product (XX), which was necessary for theformation of carbenium ion (XXI), was not detected.Dihydropyrimidines…

Studies on some compounds… 242PhOHN H 2ONH 2PhOH ONH(XXV)NH 2H +-H 2 OOPhOEtON + NH 2H(XXVI)H 3OC(XVIII)EtOOCC H 3PhNHNHOEtOOCC H 3PhON H 2NHON H 2(XXIV) (XXIII) (XV)ONHPhNHONH 2THERAPEUTIC IMPORTANCEDihydropyrimidine derivatives exhibit broad spectrum of therapeuticactivities. Since 1980’s a number of publications and patents are published for theactivity of DHPM derivatives which indicates the interest on the subject istremendously increased. 10,12 This is mainly due to the fact that the multifunctionalizeddihydropyrimidine scaffold (DHPM, “Biginelli compounds”) represents aheterocyclic system with remarkable pharmacological efficiency. In the past decades,a broad range of biological effects, including antiviral, antitumor, antibacterial andanti-inflammatory activities has been described to these partly reduced pyrimidinederivatives 47 Recently, appropriately functionalized DHPMs have emerged as orallyactive antihypertensive agents 48-50 or α1a adrenoceptor- selective antagonists. 51,52Mayer et al. 53-55have recently identified the structurally rather simple DHPM(monastrol) as a novel cell-permeable molecule. Monastrol is the only cell-permeablemolecule currently known to specifically inhibit mitotic kinesin Eg5 and can thereforebe considered as a leader for the development of new anticancer drugs. Apart fromsynthetic DHPM derivatives, several marine natural products with interestingbiological activities containing the dihydropyrimidine-5-carboxylate core haverecently been isolated. 56 Most notably among these are the batzelladine alkaloids ADihydropyrimidines…

Studies on some compounds… 243and B which inhibit the binding of HIV envelope protein gp-120 to human CD4 cells57and therefore they are potentially new leading molecules for AIDS therapy.Dihydropyrimidines have attracted considerable attention as they appearedwith Interest to possess wide range of therapeutic activities. Different activities are asunder.1. Antiviral 58-612. Antibacterial 623. Antitumor 63-654. Cardiovascular 66-685. Antiplasmal 696. Anticarcinogenic 707. Calcium channel modulator 71-738. Antihypertensive 74-769. Vasodilative 7710. Blood platelet aggregation inhibitor 78,7911. Antiinflammatory 80,8112. Analgesic 8213. Antileukemic 8314. α1a-Adrenergic receptor antagonist. 84,8515. Coronary dilatory 8616. Anti-ichemic 8717. Neuropeptide Y (NPY) antagonist 8818. Mitotic Kinesin inhibitor 8919. Metabotropic glutamate receptor antagonist 90Dhanapalan N. et al 91 prepared dihydropyrimidinones such as compound (I)which exhibited high binding affinity and subtype selectivity for the cloned humanα1a receptor. Systematic modifications of (I) led to identification of highly potent andsubtype-selective compounds such as (II) with high binding affinity (K1) 0.2 Nm forα1a receptor and greater than 1500 fold selectivity over α1b and α1d adrenoceptors.The compounds were found to be functional antagonists in human, rat and dogprostate tissues. One compound exhibited excellent to inhibit intraurethral pressure(IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogsDihydropyrimidines…

Studies on some compounds… 244Kb(DBP)/ Kb(IUP) = 40 suggesting uroselectivity for α1a-selective compounds (I) &(II).PhCOOMePhCOOMeNO 2NNN H 2OCH 3NHNOONHH 3 CNO 2OOH 3 C N OONHNH(I)(II)Calcium ion plays a vital role in a large number of cellular processes,including excitation-contraction and stimulus-secretion. 92-94 In recent years interesthas also focused on aza-analogs such as dihydropyrimidines (III) which show a verysimilar pharmacological profile to classical dihydropyridine calcium channelmodulators. 95-101O 2 NOi-PrONCONH 2C H 3NHO(III)Hidetsura Cho et al. 95 have synthesized the novel calcium channel antagonists3-N-substituted-3,4-dihydropyrimidines and 3-N-substituted-dihydropyrimidin-2(1H)102-ones were regioselectively synthesized in good yields. Efforts of Atwal K. S. et al.in this area have resulted in the discovery of dihydropyrimidines (IV) and (V) aspotent AII receptor antagonists.Dihydropyrimidines…

Studies on some compounds… 245R 1 OOCR 2 H3CCH 3EtOOCNNR 4R 3NCH 3ClNCH 3(IV)NaOOC(V)Atwal K. S. et al. 103 have described the potent antihypertensive activity of the104modestly active dihydropyrimidine calcium channel blocker. Kappe C. O. et al.synthesized the polycyclic DHPM derivatives. Muralidhar T. G. et al.105 havesynthesized several DHPM-one analogues, among this (VI) and (VII) gave excellentselectivity (>880-fold) over a1b and a1d and also showed good selectivity overseveral other recombinent human G-protein coupled receptors.FFFFOOON H 2NNHNMeOOCNNHNCH 3NH(VI)OPhH 3 CCNONH(VII)OPhCH 3Victor E.et al. 106 synthesized 5’-triphosphates of (VIII) and (IX) evaluateddirectly as reverse transcriptase (RT) inhibitors using both a recombinant enzyme andenzyme obtained and purified directly from wild-type viruses.Dihydropyrimidines…

Studies on some compounds… 246CH 3CH 3OONNHNNHHOOHOON 3(VIII)(IX)N 3Sally-Ann P.et al. 107 synthesized 4,6-Bis[(R-carbamoylethyl)thio]-1-phenylpyrazolo[3,4-d]pyrimidine and identified as a novel adenosine A1 receptorantagonist, antagonizing adenosine-stimulated cyclic adenosine monophosphategeneration in guinea pig brain slices. 108,109James and coworkers 110 reported the DHPM with 4-aryl dihydropyrimidinonesattached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective α1a receptorsubtype antagonists. Many of these compounds were also evaluated in vivo and foundto be more potent than terazosin in both a rat model of prostate tone and a dog modelof intraurethral pressure without significantly affecting blood pressure. While many ofthe compounds tested, displayed poor pharmacokinetics, compound (X) was found tohave adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs.FFONNHNHH 3 CONHOF(X)Rakesh Kumar and coworkers 111 synthesized, 5-substituted-6-azido-5,6-dihydro- 2-deoxyuridine (XI & XII) and thymidine (XIII & XIV), which exhibitedcytotoxic and antiviral activities. The compounds (XI) and (XIV) exhibited a broadspectrum of antiherpes activity against (HSV-1, HSV-2, HCMV, and VZV).Dihydropyrimidines…

Studies on some compounds… 247ROXNHXRHON 3HON(XI)O(XII)(XIII)(XIV)BrClBrClHHMeMeHOBaldev Kumar et. al. 112 have prepared some new oxo-pyrimidine derivative(XV) and reported them as potent calcium channel blockers. Abd. El-Galil and M.Abdulla93 have synthesized some fused steroidal oxo-pyrimidine derivative (XVI) andreported them as androgenic anabolic agent as well as anti-inflammatory agent.HNArCOOEtHOCH H3 CH 3N XONHMeX = O, NH, SNH(XV)(XVI)ClSalvatore B. et al 113 studied the stopped-flow fluorometry indicates thatmonastrol inhibits ADP release by forming an Eg5-ADP-monastrol complex.Alessandro 114 have studied molecular diversity in DHPM molecules byintroducing sugar molecules at different position (XVII) and effect of chirality onactivity.SugarR'OOCNHSugarNSugar(XVII)ODihydropyrimidines…

Studies on some compounds… 248Recently, Vladimir N, Belov et. al. 115 have documented enantioselectivesynthesis of the novel antiinfective TAN-1057A via aminomethyl-substituteddihydropyrimidinoneheterocycle (XVIII).CH 3RNNOONHNHNH 2(XVIII)Rajni Garg et. al. 116 suggest that the balance of hydrophobicity and a volumedependent polarizability plays a key role in the inhibition of the viral protease bythese (XIX) inhibitors.RONNR(XIX)OHSeveral potent, cell permeable 4-aryl-dihydropyrimidinones have beenidentified as inhibitors of fatty acid transporter FATP4. Christopher Blackburn et.al. 117 described that lipophilic ester substituents at the 5-position and substitution atthe para-position (optimal group -NO2 and CF3) of the 4-aryl group led to activecompounds (XX), (XXI).Dihydropyrimidines…

Studies on some compounds… 249NO 2NO 2OOHNNHSEtHNOONHCH 3ONHCH 3(XX)(XXI)NEW DRUG MOLECULES UNDER CLINICAL STUDY:Recently many new molecules which are under study from phase-I to Phase-IV clinical trials for different pharmacological action have shown that the basiccharacteristic of morpholine to behave as hidden amine has attracted many medicinalchemists to incorporate this feature in drug design. Some interesting compounds areas under.NO 2OONO CH 3HNCH 3C H 3NHCH 3Treatment of HypertensionCalcium Channel Blockers 118ONHCH 3Company Name: Merck & Co.Calcium Channel BlockersMoreover one compound 119 is very active against Non-nucleoside inhibitor ofhuman hepatitis B virus (IC50 = 53 nM for reduction of HBV DNA in humanhepatoma HepG2.2.15 cells) with low cytotoxicity in uninfected cells (CC50 = 7mcM). Compound inhibited both viral DNA and viral cores in HepG2.2.15 cells andHBV-transfected cell lines, whereas it did not affect the activity of endopolymeraseDihydropyrimidines…

Studies on some compounds… 250and had no effect on other DNA or RNA viruses. In vivo in a transgenic mouse model,oral doses of 3-100 mg/kg b.i.d. or t.i.d. for up to 28 days dose-dependently.Decreased viral DNA in the liver and plasma with efficacy comparable tolamivudine. However, unlike lamivudine, compound reduced cytoplasmic HBV coreantigen (HBcAg) in the liver of mice. Pharmacokinetic studies in mice showed rapidabsorption, 30% bioavailability and dose-proportional plasma levels.FClOName: Bay-41-4109Anti Hepatitis B Virus Drugs 120HNOCH 3BayerNNHCH 3FFONO 2OONOH 3 CNCH 3Calcium channel blocker 121OOONHH 3 C CH 3MAR-99NNOHLeukotrine Antagonist 122(Known anti-asthmatic agent, nowreported to possess anti-ulcerative andgastric antisecretory activities, whichinhibits hydrochloric acid-ethanol-,stress- and indomethacin-induced ulcersin rat.Dihydropyrimidines…

Studies on some compounds… 251NO 2CH 3OOCH 3C H 3ONONH 3 CNSCH 3Calcium Channel Blocker 123NH 2OHNNFAntifungal Agent. 124In vitro susceptibility of Candidaspecies isolated from cancer patientsagainst some antifungal agentsFlucytosine(flourocytosine)NH 2ClNAntimalarial Agent. 125N H 2NCH 3PrimethamineClOCH 3ClNHNHNNHNOImmunosuppressantsClOncolytic DrugClDihydropyrimidines…

Studies on some compounds… 252OHNNNNOHHONNNNOHDipyrimidamoleActute Myocardial infectionTreatment of Antiplatlet TherapyONOHHNCH 3NHCH 3OAntibacterial Drugs39th Intersci Conf Antimicrob AgentsChemother (Sept 26-29, San Francisco)1999, Abst F1808In vitro activity of novel 6-anilinouracilstargeted to DNA polymerase III of GrampositivebacteriaOHNCH 3CH 3O N SOCH 3Anti HIV AgentReverse Transcripase Inhibitors.Non-nucleoside HIV-1 reverse transcriptaseinhibitorCompound was active not only againstwildtypeHIV-1 strains (IC50 = 3 nM against IIIBand NL4-3 HIV-1 strains) but also showednanomolarTNK - 6123Dihydropyrimidines…

Studies on some compounds… 253With an intention of preparing the compounds possessing better therapeuticactivity, we have undertaken the synthesis of dihydropyrimidines which have beendescribed in following sections.SECTION:-6.1 SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-[ARYL-5-(3,4–DIMETHYL)-PHENYL AMINO CARBONYL]– 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.SECTION:-6.2 SYNTHESIS AND STRUCTURE ELUCIDATION OF N-PHENYL-4–[ARYL-5-(3,4 - DIMETHYL)-PHENYL AMINOCARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.SECTION:-6.3 SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-[ARYL-5-(3,4–DIMETHYL)-PHENYL AMINO CARBONYL]–6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-AMINO.Dihydropyrimidines…

Studies on some compounds… 254SECTION-6.1SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5-(3,4–DIMETHYL) – PHENYL AMINO CARBONYL] – 6–PHENYL-1,4-DIHYDROPYRIMIDINE - 2(1H)-ONES.The broad spectrums of pharmacological properties have been demonstratedby the dihydropyrimidinone nucleus. Inspired by these facts, novel dihydropyrimidinederivatives of type (XI) have been synthesized by the condensation of N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide with urea and aryl carboxaldehydes inthe presence of catalytic amount of con. HCl.H 3 CCOH 3NHOUrea / R-CHOMethanol / HClH 3 CCORCompound-(XI)Type- (XI)H 3NHNHNHOR= ArylThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (XIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (XIa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations.(Chapter-8)Dihydropyrimidines…

Studies on some compounds… 255Reaction SchemeH 3 C+H 3 CNH 2H 3 COOOTolueneRefluxOHH 3 CCOH 3NH+ +ON H 2NH 2OREthanolHydrochloric acidH 3 CCORH 3NHNHNHOType-(XI)R=ArylDihydropyrimidines…

Studies on some compounds… 256IR SPECTRAL STUDIES OF 4-[(p-METHOXYPHENYL) -5-(3,4–DIMETHYL) – PHENYL AMINO CARBONYL] – 6–PHENYL-1,4-DIHYDROPYRIMIDINE - 2(1H)-ONES.90.0%T80.070.060.050.040.030.020.02865.02958.63081.0 3025.03397.0H 3 CCH 3NHC H 3OONHHNHO1572.01710.71605.01677.01474.51371.01378.01439.81534.31144.71205.41279.71058.0904.6463.8661.5690.5756.04000.03000.0 2000.0dhpm(simple)1800.01600.01400.01200.01000.0800.0600.0400.01/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str.(asym.) 2958 2975-2950 126-CH3 C-H str.(sym) 2865 2880-2860 "C-H def.(asym.) 1439 1470-1435 "C-H def.(sym.) 1378 1390-1370 "Aromatic C-H str. 3081 3090-3030 127C=C str. 1534 1540-1480 "Pyrimidine C=C str. 1572 1580-1520 "Moiety C-H i.p. def. 1057 1125-1000 "C-H o.o.p. def. 842 835-810 "Amide -NH Str. 3397 3410-3380 126-NH def. 1605 1635-1595 "Carbonyl -C=O Str. 1710 1700-1725 "Amide -C=O Str. 1677 1690-1660 "Ether Ar-O-C (sym.) 1068 1075-1010 "Dihydropyrimidines…

Studies on some compounds… 257PMR SPECTRAL STUDIES OF 4-[(p-METHOXYPHENYL)-5-(3,4–DIMETHYL) – PHENYL AMINO CARBONYL] – 6–PHENYL-1,4-DIHYDROPYRIMIDINE - 2(1H)-ONES.C H 3OH 3 CCOHH 3NHNHNHOInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer(300 MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 2.12 6H doublet 2 (CH 3 ) moiety2 3.82 3H Singlet Ar-OCH 33 5.38 1H Singlet -CH (pyrimi.)4 6.82-7.22 12H multiplet Ar-H5 7.42 1H singlet -NH (pyrimi.overlapped)6 7.78 1H singlet -NH (pyrimi.)7 8.82 1H singlet -NHCODihydropyrimidines…

Studies on some compounds… 258MASSS PECTRAL STUDIES OF 4-[(p-METHOXYPHENYL)-5-(3,4–DIMETHYL) – PHENYL AMINO CARBONYL] – 6–PHENYL-1,4-DIHYDROPYRIMIDINE - 2(1H)-ONES.H 3 COH 3 CH 3 CNHONHNHOm/z = 427.49Dihydropyrimidines…

Studies on some compounds… 259MASS FRAGMENTATIONH 3 CCH 3NHONCO +0H 3 CCH 3ONHO+0+0H 3 CNHOm/z = 293CH 3m/z = 281m/z = 237OH 3 CO+0H 3 CONHm/z = 264NCO+0H 3 CCH 3NHONHNHO+0N H 2ONHNHO( M. I. P.) = (B. P.) m/z = 428m/z = 321NHNm/z = 158+H 3 CONH 2 +0m/z = 1370H 3 COONHNH+N 0Hm/z = 385+0H 3 COH 3 CNHNHNHm/z = 398OOCH 3+0NH+0H 2Cm/z = 135NHm/z = 98ODihydropyrimidines…

Studies on some compounds… 260EXPERIMENTALSYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5-(3,4–DIMETHYL) – PHENYL AMINO CARBONYL] – 6–PHENYL-1,4-DIHYDROPYRIMIDINE - 2(1H)-ONES.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 3,4-DIMETHYL PHENYL) – 3 –OXO – 3 – PHENYLPROPANAMIDE.A mixture of Ethyl benzoyl acetate (20 gm, 0.1 mol) and 3,4-dimethylaniline(15 gm, 0.12 mole) in toluene was refluxed for 14 hr. ethanol was removed usingDean & Stark azeotropic assembly. The mixture was cooled to room temperature,washed the reaction mixture with dil HCl and than washed with water. Distilled outtoluene under vaccume. The resulting residue was crystallized into the n-Hexane.Yield 80 %, m. p. 112˚C.[B] PREPARATION OF 4 – METHOXY PHENYL [5 - (3,4 – DIMETHYL) –PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 - DIHYDROPYRIMIDINE -2(1H) –ONES.A mixture of urea (1.0 gm, 0.01 mole), 4-methoxy benzaldehyde (1.5 gm, 0.01mole) and N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide (3.0 gm, 0.01 mol) in25 ml of ethanol containing few drops of concentrated hydrochloric acid was refluxedfor 10 hrs. The solution was allowed to stand for 12 hrs. at room tempeture and theresulting solid mass separated was filtered and crystallized from DMF-ethanolmixture. Yield - 68%, m.p.252˚C, [C 26 H 25 N 3 O 3 ; required: C, 73.05; H, 5.89; N, 9.83%, found: C, 73.09; H, 5.95; N, 9.88 %.Similarly, other 4 - aryl [5 - (3,4 – dimethyl) – phenyl amino carbonyl] – 6 –phenyl- 1,4 - dihydropyrimidine -2(1H) –ones were, prepared. The physical data arerecorded in Table No.11Dihydropyrimidines…

Studies on some compounds… 261TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)[C] BIOLOGICAL EVALUATION OF 4 - ARYL [5 - (3,4 – DIMETHYL) –PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 - DIHYDROPYRIMIDINE -2(1H) –ONES.Antimicrobial testing were carried out as described in Chapter-8. The zones ofinhibition of test solutions are recorded in Graphical Chart-11a, Table-11a.PageNo.-387, 388. Result and discussion is given on page no.:- 389.Dihydropyrimidines…

Studies on some compounds… 262● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Dihydropyrimidines…

Studies on some compounds… 263SECTION:-6.2SYNTHESIS AND STRUCTURE ELUCIDATION OF N-PHENYL, 4 -ARYL-[5-(3, 4 -DIMETHYL)-PHENYL AMINO CARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE- 2(1H)-ONES.Much interest have been focused around dihydropyrimidines derivativesbecause of their wide variety of pharmacological properties and industrialapplications. In view of these findings and achieve to better drug potency, we havesynthesized novel dihydropyrimidine derivatives of type- (XII) by the condensation ofN-(3,4-dimethyl phenyl)-3-oxo-3-phenylpropanamide with N-phenylurea and arylcarboxaldehydes in the presence of catalytic amount of HCl.H 3 CCOH 3NHN-phenyl urea / R- CHOMethanol / HClOH 3 CCORCompound-(XII)Type-(XII)H 3NHNHNOR= ArylThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (XIIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (XIIa-j) have been compared with standarddrugs viz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(chapter-8).Dihydropyrimidines…

Studies on some compounds… 264Reaction SchemeH 3C+H 3 CNH 2H 3COOOTolueneRefluxOHO+H 3CCH 3NHO+H 2 NHNOREthanolHydrochloric acidH 3CCORH 3NHNNHOType-(XII)R=ArylDihydropyrimidines…

Studies on some compounds… 265IR SPECTRAL STUDIES OF N-PHENYL- 4-[(p-METHOXYPHENYL -5-(3, 4 -DIMETHYL)-PHENYL AMINO CARBONYL]–6 – PHENYL - 1, 4 –DIHYDROPYRIMIDINE-2(1H)-ONES.100.0%T90.080.0H 3 CCH 3NHC H 3OOHN70.060.050.040.030.020.02874.73047.02958.03072.03396.41578.0NH1362.01388.71456.21689.51513.11706.91625.9O1252.71101.3445.5548.7619.1634.5751.2814.9695.34000.03000.02000.01800.01600.01400.01200.01000.0800.0600.0400.01/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequencyrange:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str.(asym.) 2958 2975-2950 126-CH3 C-H str.(sym) 2874 2880-2860 "C-H def.(asym.) 1456 1470-1435 "C-H def.(sym.) 1388 1390-1370 "Aromatic C-H str. 3047 3090-3030 127C=C str. 1513 1540-1480 "Pyrimidine C=C str. 1578 1580-1520 "Moiety C-H i.p. def. 1101 1125-1000 "C-H o.o.p. def. 814 835-810 "Amide -NH Str. 3396 3410-3380 126-NH def. 1625 1635-1595 "Carbonyl -C=O Str. 1706 1700-1725 "Amide -C=O Str. 1689 1690-1660 "Ether Ar-O-C (sym.) 1090 1075-1010 "Dihydropyrimidines…

Studies on some compounds… 266PMR SPECTRAL STUDIES OF N-PHENYL- 4-[(p-METHOXYPHENYL) - 5-(3, 4 -DIMETHYL)-PHENYLAMINO CARBONYL] – 6 – PHENYL - 1, 4 –DIHYDRO PYRIMIDINE-2(1H)-ONES.C H 3OH 3 CCH 3NHOHNNHOInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 2.15 6H doublet 2 (CH 3 ) moiety2 3.86 3H Singlet Ar-OCH 33 5.35 1H Singlet -CH (pyrimi.)4 622-8.25 17H multiplet Ar-H5 9.01 1H singlet -NH (pyrimi.)6 10.12 1H singlet -NHCODihydropyrimidines…

Studies on some compounds… 267MASS SPECTRAL STUDIES OF N-PHENYL- 4-[(p-METHOXYPHENYL) - 5-(3, 4 -DIMETHYL)-PHENYLAMINO CARBONYL] – 6 – PHENYL - 1, 4 –DIHYDRO PYRIMIDINE-2(1H)-ONES.H 3 COH 3 CH 3 CNHONNHOm/z = 503.59Dihydropyrimidines…

Studies on some compounds… 2680MASS FRAGMENTATIONH 3 CCO ++H 3 CO0H 3 CH+3 C+OH 3 CNH H 3C0OHm/z = 121+3 CNH N+ NNH NH00N OHN ONHm/z = 503m/z = 250m/z = 367( M. I. P.)H 3m/z = 148NHNHN+0O+0m/z = 157(B. P.)H 3 CCNHOH 3m/z = 251+0H 3 CCH 3NHNHNm/z = 473O+0ONHNNHONCO+0NHm/z = 368Om/z = 264H 3 CCNHOH 3m/z =293NC+O 0Dihydropyrimidines…

Studies on some compounds… 269EXPERIMENTALSYNTHESIS AND STRUCTURE ELUCIDATION OF N-PHENYL-4-ARYL -[5-(3,4– DIMETHYL) – PHENYL AMINO CARBONYL]– 6–PHENYL-1,4-DIHYDRO PYRIMIDINE - 2(1H)-ONES.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 3,4-DIMETHYL PHENYL) – 3 –OXO – 3 – PHENYLPROPANAMIDE.Pls. refer chapter-6, Section-6.1, Page No.-260[B] PREPARATION OF N-PHENYL- 4 – METHOXYPHENYL [5 - (3,4 –DIMETHYL) – PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 -DIHYDRO PYRIMIDINE -2(1H) –ONES.A mixture of n-phenyl urea (1.36 gm, 0.01 mole), 4-methoxy benzaldehyde (1.5gm, 0.01 mole ) and N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide (2.67 gm,0.01 mole) in 15 ml of ethanol containing few drops of concentrated hydrochloric acidwas refluxed for 7 hrs. The solution was allowed to stand for 12 hrs. at roomtemperature and the resulting solid mass separated was filtered and crystallized fromdioxane., Yield- 60%, m.p.185˚C, [C 32 H 29 N 3 O 3 ; required: C,76.32; H, 5.80; N,8.34%, found: C, 76.35; H, 5.78; N, 8.32 %].Similarly, other N-phenyl-4 - aryl [5 - (3,4 – dimethyl) – phenyl aminocarbonyl] – 6 – phenyl- 1,4 - dihydropyrimidine -2(1H) –ones, were prepared. Thephysical data are recorded in Table No.12TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8)Dihydropyrimidines…

Studies on some compounds… 270[C] BIOLOGICAL EVALUATION OF N-PHENYL- 4 - ARYL [5 - (3,4 –DIMETHYL) – PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 -DIHYDRO PYRIMIDINE -2(1H) –ONES.Antimicrobial testing were carried out as described in Chapter-8. The zonesof inhibition of test solutions are recorded in Graphical Chart-12a, Table-12a. PageNo. - 390, 391. Result and discussion is given on page no. - 392.Dihydropyrimidines…

Studies on some compounds… 271● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Dihydropyrimidines…

Studies on some compounds… 272SECTION:-6.3SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL - [5 - (3, 4 –DIMETHYL)-PHENYL AMINO CARBONYL]–6 – PHENYL - 1, 4 –DIHYDROPYRIMIDINE-2(1H)-AMINO.Pyrimidine derivatives have been reported to possess various pharmacologicalactivities like antibacterial, antifungal, etc. In order to achieve better drug potency, wehave synthesized pyrimidine derivatives of type (XIII) by the condensation of N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide with guanidine and aryl carboxaldehydes in the presence of catalytic amount of potassium carbonate.H 3 CCOH 3NHGuanidine-HCl / R-CHOODMF/ K 2 CO 3H 3 CCORCompound-(XIII)Type-(XIII)H 3NHNHNHNHR= ArylThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (XIIIa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (XIIIa-j) have been compared with standarddrugs viz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(Chapter-8).Dihydropyrimidines…

Studies on some compounds… 273Reaction SchemeH 3C+H 3CNH 2H 3 COOOToluene RefluxOHO+H 3CCH 3NHO+N H 2NH 2. HClNHRDMF K 2CO 3H 3 CCORH 3NHNHNHNHType-(XIII)R=ArylDihydropyrimidines…

Studies on some compounds… 274IR SPECTRAL STUDIES OF 4-(-p-METHOXY PHENYL) -5 - (3, 4–DIMETHYL) -PHENYL AMINO CARBONYL] –6–PHENYL-1,4-DIHYDROPYRIMIDINE-2(1H)-AMINO.C H 3OH 3 CCOHH 3NHNHNHNHInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.ObservedReportedAlkane C-H str.(asym.) 2921 2975-2950 126-CH3 C-H str.(sym) 2840 2880-2860 "C-H def.(asym.) 1441 1470-1435 "C-H def.(sym.) 1401 1390-1370 "Aromatic C-H str. 3075 3090-3030 127C=C str. 1509 1540-1480 "Pyrimidine C-H i.p. def. 1088 1125-1000 "Moiety C-H o.o.p. def. 828 835-810 "Amide -NH Str. 3314 3410-3380 "-NH def. 1631 1635-1595 126Carbonyl -C=O Str. 1677 1700-1725 "Amide -C=O Str. 1654 1690-1660 "Ether Ar-O-C (sym.) 1088 1075-1010 "Dihydropyrimidines…

Studies on some compounds… 275PMR SPECTRAL STUDIES OF -4-[(p-METHOXYPHENYL)-5-(3,4-DIMETHYL)-PHENYLAMINO CARBONYL] – 6 – PHENYL - 1, 4 –DIHYDRO PYRIMIDINE-2(1H)-AMINO.C H 3OH 3 CCH 3NHOHNHNHNHInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 2.08 6H doublet 2 (CH 3 ) moiety2 3.88 3H Singlet Ar-OCH 33 5.25 1H Singlet -CH (pyrimi.)4 6.12 1H Singlet -NH (guanidi.)5 6.31-7.80 12H multiplet Ar-H6 7.88 1H doublet -NH (pyrimi.)7 8.22 1H Singlet -NH (pyrimi.)8 9.85 1H Singlet -NH (-NHCO)Dihydropyrimidines…

Studies on some compounds… 276MASS SPECTRAL STUDIES OF-4-[(p-METHOXYPHENYL)-5-(3,4-DIMETHYL)-PHENYLAMINO CARBONYL]– 6 – PHENYL - 1, 4 –DIHYDROPYRIMIDINE-2(1H)-AMINO.H 3 COH 3 CCOH 3NHNHNHNHm/z = 426Dihydropyrimidines…

Studies on some compounds… 277MASS FRAGMENTATIONO -O -H 3 CCOOH 3NHNHNHNHNHNHNHm/z = 398m/z = 385H 3 CO+0H 3 CO+0H 3 CCH 3NHONHH 3 CO+0H 3 CNHNHNHNHNHm/z = 307m/z = 108m/z = 426(M.I.P.) = (B. P.)H 3 CCO+0NHOH 3 NH+CH 3 0NH+ OH0m/z = 94m/z = 223m/z = 280Dihydropyrimidines…

Studies on some compounds… 278EXPERIMENTALSYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL -[5-(3,4–DIMETHYL) – PHENYL AMINO CARBONYL] – 6–PHENYL-1,4-DIHYDROPYRIMIDINE - 2(1H)-AMINO.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 3,4-DIMETHYL PHENYL) – 3 –OXO – 3 – PHENYLPROPANAMIDE.Pls. refer chapter-6, Section-6.1, Page No.-260[B] PREPARATION OF N-PHENYL- 4 – METHOXYPHENYL [5 - (3,4 –DIMETHYL) – PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 -DIHYDRO PYRIMIDINE -2(1H) –AMINO.A mixture of Guanidine-HCl (2.0 gm, 0.02 mole), 4-methoxy benzaldehyde(1.36 gm, 0.01 mole) and N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide (2.67gm, 0.01 mole) in 15 ml of DMF containing pinch of potassium carbonate wasrefluxed for 14 hrs. The solution was allowed to stand for 12 hrs. at room tempetureand the resulting solid mass separated was filtered and washed with dil. HCl thencrystallized from dioxane.Yield-58%, m.p.-166˚C, [C 26 H 26 N 4 O 2; required: C, 73.22;H, 6.14; N, 13.14 %, found: C, 73.20; H, 6.18; N, 13.12 %].Similarly, other N-phenyl-4 - aryl [5 - (3,4 – dimethyl) – phenyl aminocarbonyl] – 6 – phenyl- 1,4 - dihydropyrimidine -2(1H) – amino, were prepared. Thephysical data are recorded in Table No.13TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8).Dihydropyrimidines…

Studies on some compounds… 279[C] BIOLOGICAL EVALUATION OF N-PHENYL- 4 - ARYL [5 - (3,4 –DIMETHYL) – PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 -DIHYDRO PYRIMIDINE -2(1H) –AMINO.Antimicrobial testing were carried out as described in Chapter-8,The zones ofinhibition of test solutions are recorded in Graphical Chart-13a, Table- 13a. PageNo.-393, 394. Result and discussion is given on page no. - 395.Dihydropyrimidines…

Studies on some compounds… 280● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Dihydropyrimidines…

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Studies on some compounds… 28789. Khanina E. L., Siliniece G., Ozols J., Duburs G., Kimenis A.;Khim.-Farm. Zh. 12 72–74 (1978).90. Kastron V. V., Vitolin R. O., Khanina E. L., Duburs G., Kimenis A.;Khim.-Farm. Zh. 21 948–952 (1987).91. Dhanapalan, Nagarathnam.;J. Med. Chem., 2, 4764-4777 (1999).92. Kretsinger R. H.;Adv. Cyclic Nucleotide Res., 11, 1 (1979).93. Rosenberger L. B., Triggle D. J.;Calcium and Drug Action; G. B. Weiss, Ed.; Plenum Press: New York, 1978.94. Putney Jr., J. W.;Pharmacol. Rev., 30, 209 (1978).95. Cho H., Ueda M., Shima K., Mizuno A., Hayashimatsu M., Ohnaka Y.,Takeuchi Y.,Hamaguchi M., Aisaka K., Hidaka T., Kawai M., Takeda M.,Ishihara T., Funahashi K.;J. Med. Chem., 32, 2399 (1989).96. Atwal K., Rovnyak G. C., Schwartz J., Moreland S., Hedberg A., GougoutasJ.Z., Malle M. F., Floyd D. M.;J. Med. Chem., 33, 1510 (1990).97. Atwal K. S., Rovnyak G. C., Kimball S. D., Floyd D. M., Moreland S.,SwansonB. N.,Gougoutas J. Z., Schwartz J., Smillie K. M., Malley M. F.;J.Med. Chem., 33, 2629 (1990).98. Atwal K. S., Swanson B. N., Unger S. E., Floyd D. M., Moreland S., HedbergA.,O´Reilly B. C.;J. Med. Chem., 34, 806 (1991).99. Grover G. J., Dzwonczyk S., McMullen D. M., Normadinam C. S., Sleph P.G., Moreland S. J.;J. Cardiovasc. Pharmacol., 26, 289 (1995).100. Rovnyak G. C., Kimball S. D., Beyer B., Cucinotta G., DiMarco J. D.,Gougoutas J., Hedberg A., Malley M., McCarthy J. P., Zhang R., Moreland S.;J. Med. Chem., 38, 119 (1995).101. Triggle D. J., Padmanabhan S.;Dihydropyrimidines…

Studies on some compounds… 288Chemtracts Org. Chem., 8, 191 (1995).102. Atwal K. S., Ahmed S. Z., Eileen B. B., Delaney C. L., Dickinson K. E.,Francis N.F., Aners H., Miller A. V., Suzanne Moreland, Brian C. O’Reilly,Thomas R. Schaeffer;J. Med. Chem., 35, 4751-4763 (1992).103. Atwal K. S., Swanson, B. N., Unger S. E., Floyd D. M., Moreland S., HedbergA., O´Reilly B. C.;J. Med. Chem., 34, 806 (1991).104. Kappe C. O., Birgit J., Tetiana P.;Molecules, 5, 227-239 (2000).105. Muralidhar T. G., Dhanapalan N., Mohammad R. M., Bharat L., Wai C. W.,George C., Sriram T., Shou Wu M., Fengqi Z., Wanying S., Dake T.,Quanrong S., Jack Z., John M. W.;J. Med. Chem., 42, 4778-4793 (1999).106. ictor E. Marquez, Abdallah Ezzitouni, Pamela Russ, Maqbool A. Siddiqui,Harry Ford, Jr. Ron J. Feldman, Hiroaki Mitsuya, Clifford George, Jr. JosephJ. Barchi;J. Am. Chem. Soc., 120, 2780-2789 (1998).107. Sally-Ann Poulsen, Ronald J. Quinn;J. Med. Chem., 39, 4156-4161 (1996).108. Davies L. P., Brown D. J., Chow S. C., Johnston G. A. R.;Neurosci. Lett., 41, 189-193 (1983).109. Davies L. P., Chow S. C., Skerritt J. H., Brown D. J.,Johnston G. A. R.;Life Sci., 34, 2117-2128 (1984).110. James C. Barrow P.;J. Med. Chem., 43, 2703-2718 (2000).111. Kumar R.;Bioorganic & Medicinal Chemistry Letters, 12, 275–278 (2002).112. Baldev Kumar, Balbir Kaur and Jatinder Kaur.;I. J. Chem., Vol. 41B, 1526-1530 (2002).113. Salvatore DeBonis, Jean-Pierre Simorre, Isabelle Crevel, Luc Lebeau et. al.;Biochemistry, 42, 338-349 (2003).114. Alessandro D., Alessandaro,M.;Dihydropyrimidines…

Studies on some compounds… 289Molecular Diversity, 6, 261-270 (2003).115. Vladimir N., Belov, Michael Brands et. al.;Tetrahadron, 60, 7579-7589 (2004).116. Rajni Garg and Disha Patel.;Bioorganic & Medicinal Chemistry Lett., 15, 3767-3770 (2005).117. Christopher Blackburn, Bing Guan, James Brown et. al;Bioorganic and Medicinal Chemistry Lett., 16, 3504-3509 (2006).118. Drug Data Report; 8(1), 35 (1986).119. Drug Data Report, 10(3), 200 (1988).120. Drug Data Report, 24(2), 165, (2002).121. Drug Data Report, 8(5), 465 (1986).122. Drug Data Report,10(10), 826 (1988).123. Drug Data Report,10 (11), 899 (1988).124. Clin Microbiol Infect 9, 1504 (2003).125. Lancet. 361 (9357), 577 (2003).126. V. M. Parikh;Absorption spectroscopy of organic molecules, Addition-Wesley Pub. Co.London 243, 258 (1978). A. Hand book of spectroscopic data by B. D.Mishtry; 1st ed. ABD Press Jaipur 11-36 (2000).127. A. R. Kartizky and R. Alans Jones;J. Chem. Soc., 2942 (1960). Introduction of Infra red and Raman spectroscopyby Norman B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy.Academic Press (1975).Dihydropyrimidines…

CHAPTER - 7STUDIES ONTHIAZOLOPYRIMIDINES

Studies on some compounds… 290INTRODUCTIONThiourea itself was one of the first new drug employed to depress, theclinically over active thyroid in thyrotoxicosis 1 but some of the cyclic thioureideshave been found better suited. All of these are prone of produce adverse reduction insusceptible patients and found more potent and less likely to produce side effect and isbeing used widely. 2Generally pyrimidine derivatives such as 2-hydroxy pyrimidine, 2-mercaptopyrimidine and 2-amino pyrimidine are studied. Pyrimidines have been isolated fromthe hydrolysis of the nucleic acid.Pyrimidines are among those molecules that make life possible, have beensome of the building blocks of DNA and RNA. Several analogs of pyrimidines havebeen used as compounds that interfere with the synthesis and functioning of nucleicacids e.g. fluorouracil, which has been used in cancer treatment. Also there are somethiouracil derivatives, which produce adverse reduction in susceptible patients andfound more potent and less likely to produce side effects and is being widely used.There are several other important groups of pyrimidines with medicinal uses.Pyrimidine ring carrying various substituents may be built up from two orthree aliphatic fragments by the principle synthesis or by a variety of other synthesis,which are complimentary rather than alternative to it. A second type of synthesis isthe isomerisation or break down of another heterocycles such as hydration of purinebut such roots are frequently used.Pyrimidine is best considered as a resonance hybrid to which the unchargedequivalent Kekule structures 1 and 1a and charged structures 1b and 1g contribute.The self consistent p (pi) electron densities required for the ground state of pyrimidineare 0.776, 0.825 and 1.103 for positions 2, 4 and 5 respectively. Despite considerablelocalization of p (pi) electrons at nitrogen atoms of pyrimidines, the ring system isstill sufficiently aromatic to possess substantial stability. This is great advantage in theprimary synthesis of pyrimidines.Thiazolopyrimidines…

Studies on some compounds… 291NNN+N+NNN1 1a1b 1cN+ NNN+N+NNN+N1d 1e 1f1gFrom the theoretical view point, it is essential to predict the structure, bindingproperties, chemical reactivity, etc. of dihydro compounds from the number andpositioning of nitrogen atoms in the ring, as well as from the disposition of doublebonds. Such quantum mechanical calculations also enable an evaluation of the degreeof aromatic character in potential “homoaromatic” and “antiaromatic” isomers.Availability of novel model compounds for verifying these predictions would open upnew horizons in theoretical heterocyclic chemistry, particularly in clarifying thestructures leading to spontaneous isomerization of a derivative or in verifying itsredox properties.From the biochemical point of view, 1,4-dihydropyrimidines are of intenseinterest because of presence of this group at the active site of the “hydrogentransferring coenzyme” NADH (reduced nicotinamide adenine dinucleotide). Thisnucleotide, a central participant in metabolic processes in living organisms,participates in the reduction of various unsaturated functionalities.Despite the importance of dihydroazines (particularly those containing the 1,4-dihydropyrimidine and dihydropyridine moiety 3 for clarifying a wide range oftheoretical, medicinal and biological problems, the chemistry of this group ofcompounds is still extremely spotty. 4-8 A deeper knowledge of the behavior of thisclass of compounds is, therefore, desirable. From the theoretical view point, it isessential to predict the structure, binding properties, chemical reactivity, etc. ofdihydro compounds from the number and positioning of nitrogen atoms in the ring, aswell as from the position of double bonds.Thiazolopyrimidines…

Studies on some compounds… 292In the area of drug development, dihydroazines show great promise,particularly since the 4-aryldihydropyridines exhibit powerful vasodilation activity viamodifying the calcium ion membrane channel,9-13 additionally; dihydropyridines havebeen found to actively transport medication across biological membranes. 14Until recently, most of the information available on dihydroazines centeredaround dihydropyridines, with very little data extending to the relateddihydropyrimidines.This lacuna has motivated our deep involvement in developingdihydropyrimidines chemistry, particularly dihydropyrimidines containing nosubstituents on the ring nitrogen. 15SYNTHETIC ASPECTLiterature survey reveals that several publication and patents described thesynthesis of dihydropyrimidinethiones as under.1. Polyphosphate ester (PPE) was utilized for the Biginelli's condensation. PPEserves as an excellent reaction mediator in the three component Biginelli reaction.16PPE is one of the phosphate-based reagents that are related to polyphosphoric acid(PPA). In contrast to PPA, PPE is aortic and soluble in organic media.(I)OR 3O+R 2OCHOX+ N H2 NH 2PPE, refluxR 1OH 3 CONHR 2(I)NHX2. Indium (III) chloride was emerged as a powerful Lewis catalyst impartinghigh region and chemo selectivity in various chemical transformations. Ranu C. etal. 17 described a simple synthesis of DHPM-2-(1H)-thione derivatives, (II) usingindium (III) chloride (10 mol %) as a catalyst from an aldehyde, b-dicarbonylcompound and thiourea in THF.Thiazolopyrimidines…

Studies on some compounds… 293OR 3O OR 1 R 2+ R 3 CHO +SH 2 N NH 2InCl 3R 2(II)R 1NHNHS3. DHPM was prepared from three component b-diketone, aldehyde and thioureacoupling in ethanol catalyze by indium(III) tribromide (InBr3) 18,19This modifiedone-pot Biginelli condensation provided not only simple preparation but also thismodified Biginelli reaction was oxygen-bridge (III).4. Silica Sulfuric acid efficiently catalyzes the three component Biginelli reactionbetween an aldehyde, a,b-cabonyl compound, and thiourea in ethanol to afford thecorresponding dihydropyrimidines in high yield.20 The catalyst is reusable and can beapplied several times without any decrease in the yield of the reaction (IV).EtOOCC H 3+OPhCHO+SSilica H 2 SO 4H 2 N NH 2EtOOCC H 3PhNH(IV)NHS5. Subhas D. Bose et al. 21 describe a general and practical route for the Biginellicyclocondensation reaction using cerium (III) chloride (CeCl3) heptahydrate as thecatalyst. Three different sets of reaction conditions were examined (i) traditionalethanol reflux (ii) water reflux and (iii) solvent-free conditions. This is a novel, onepotcombination that not only preserves the simplicity of Biginelli’s one-pot reactionbut also consistently produces excellent yields of the DHPM-2(1H)-thiones (V).ORORR 1 HO+ONH 2CeCl 3 .H 2 OR 1ONHR 2ON H 2SR 2NH(V)SThiazolopyrimidines…

Studies on some compounds… 2946. Shrinivas et al. 22 developed iodine catalyzed one-pot synthesis of 3,4-6.dihydropyridin-2(1H)-thiones (VI) This procedure involves three componentcyclocondensation of aldehydes, 1,3-dicarbonyl compounds and thiourea to afford thecorresponding dihydropyrimidinethiones in high yield.OH 3 CH 3 COSIodine+ R CHOC H 3O+H 2 N NH 2OOH 3 CRNH(VI)NHS7. De. S. K. et al. 23 synthesized novel one pot Biginelli-type reaction. Aromaticaldehydes with b-dicarbonbyl compound and thiourea in presence of catalytic amountof 5 % of Sc (OTf) 3 at 100 o C (VII).OORR 2O+R 1OSR CHO +H 2 N NH 2Sc(OTf) 3100 0 CR 2OR 1NHNHS(VII)8. John Mabry et al. 24 synthesized different DHPMs via enamine intermediatesusing L-praline methyl ester hydrochloride found to be an effective catalyst forassembling dihydropyrimidine (VIII) thiones under mild condition.OORR 2+R 3 OR 1CHO+SH 2 N NH 2L-prolineCH 3 OHR 2OR 1(VIII)NHNHS9. Zhang X et al. 25 developed a novel series of 4-substituted 3,4-dihydropyrimide-2(1H)-thiones (IX) employing magnesium perchlorate as anefficinet catalyst under ultrasound irradiation.Thiazolopyrimidines…

Studies on some compounds… 295OOR 1R 3O+R 2OR 1CHO+SH 2 N NH 2[Mg(ClO 4 ) 2 ]CH 3 OHR 3OR 2NHNHS(IX)10. Some Biginelli compounds were synthesized by using a photochemistrymethod. The Biginelli three component cyclocondensation reaction in THF mediumusing a mixture of b-ketoesters or b-diketone, aryl aldehyde and thiourea underirradiation with a tungsten lamp light to gave DHPM-2-(1H)-thiones 26 (X).11. A practical and green chemistry approach towards synthesis of DHPM-2-(1H)-thione without any solvent or catalyst. This method was developed by Ranu C.et al. 27 Title compound was prepared from three component b-diketone, aldehyde andthiourea was heated under stirring at 100-105 0 C afford the corresponding DHPM-2-(1H)-thione (XI) in high yield (82%) and purity (> 95%).OR 3OOR 1 R 2S100-105 R+2NHR 3 CHO + 0 CH 2 N NH 21 hr.R 1NH(XI)S12. Recently, Wang L. et al. 28-30 developed novel one pot Biginelli-type reaction.Aromatic and aliphatic aldehydes with b-dicarbonbyl compound and thiourea inpresence of catalytic amount of 5 % of Yb (OTf) 3 at 100 0 C for 60-90 minute undersolvent free condition proceeded smoothly to afford the corresponding DHPM thione(XII).Thiazolopyrimidines…

Studies on some compounds… 296OR 3O OS Yb(OTf)+ R 3 CHO +3R 2NH100 0 CR H 2 N NH 2R N S1R 21H(XII)ATWAL MODIFICATIONApart from the traditional Biginelli condensation, there are only a few othersynthetic methods available that lead to DHPMs. Since most of these protocols lackthe experimental and conceptual simplicity of the Biginelli one-pot, one-stepprocedure, none of these have any significance today or can compete with the originalBiginelli MCR approach. One noticeable exception is the so-called “Atwalmodification” of the Biginelli reaction. 31-33 Here, an enone first condensed with asuitable protected urea or thiourea derivative under almost neutral conditions.O ArO ArNHR H2 NaHCO R 1N13DMFR+ HN SRR 2 N SR 2 OHSTRUCTURAL VARIATION OF REACTIONThe original cyclocondensation reaction has been extended widely to includevariation in all three components. If these, the aldehydes component has been variedto the largest extent and now includes not only many aromatic 34-48 but also aliphatic 35,36, 43, 49-52 and heterocyclic aldehydes 35,43,50, 53-56 can also be used. Particular interest isreaction where the aldehydes component is derived from a carbohydrate. In suchreaction dihydropyrimidines having a sugar-like moiety at position four (C-nucleosideanalogs) i.e. (I) or (II) are obtained.Thiazolopyrimidines…

Studies on some compounds… 297C CH 3O OH 3COOC H 3MeOOCOONHOHH 3CH 3(I)NHSH 3CNH(II)SApart from common alkyl acetoacetates which are employed frequently as theb-ketoester components, other acetoacetic acid such as benzyl acetoacetate, 49,57 (-)-methyl acetoacetate, 57 b-chloroethyl acetoacetate, 58 2-furanylmethyl acetoacetate, 59and ethylthio acetoacetate 59 have been used successfully in the Biginelli reaction;benzoylacetic acid esters react analogously to form (III). Similarly, ethyl 4-bromoacetoacetate 55 and ethyl trifluoromethyl acetoacetate afford the corresponding 6-functionalized dihydropyrimidines (IV).C H 3OPhHC H 3OPhHONHONHPhNH(III)SF 3CNH(IV)SPrimary, secondary and tertiary acetoacetamides have been used in place ofester to produce pyrimidine-5-carboxamides (V). 38,48,60-63 It should be emphasized thatmonosubstituted thioureas from exclusively N-1 substituted dihydropyrimidines ofNH35,40, 49,50,54,59,61,63-67type (VI).H 3CH 3CONH 3CPhNH(V)HNHSC H 3OPhH 3C N SHONHR(VI)Thiazolopyrimidines…

Studies on some compounds… 298In addition to solid-phase adaptions of the traditional three-componentBiginelli condensation, solid-phase variations of the “Atwal modification” of theBiginelli reaction have also been reported. Robinett et al. 68 have disclosed thesynthesis of a 648-member combinatorial library of 1,4-dihydropyrimidines(IX).Towards this end, polymer-bound acetoacetate (VII) was subjected toKnoevenagel condensation with aromatic aldehydes, followed by condensation withisothioureas. The resulting polymer-bound 1,4-dihydropyrimidines (VIII) werecleaved from the resin with 50% TFA to produce carboxylic acid (IX).pOOPhH 3 C CH 3OHpOOC H 3PhOHNN H 2SHBrRppOH 3COHPhNHNSR(VII)(VIII)OHPhTFAONH 3 CNHSR(IX)One other novel approach to DHPMs has been described by Shutalev et al. 69 isoutlined below. This synthesis is based on the condensation of readily available R-tosyl-substituted thioureas (X) with the (in situ prepared) enolates of acetoacetates or1,3-dicarbonyl compounds. The resulting hexahydropyrimidines (XI) need not to beisolated and can be converted directly into DHPMs (XII). This method worksparticularly well for aliphatic aldehydes and thioureas and produces high overallyields of the desired target compounds.Thiazolopyrimidines…

Studies on some compounds… 299H 2 NNH 2(X)SR-CHOH 2 O, TsHTsRN H 2NHSR 1OR 2ONaH, MeCN(XI)OR 1HOR 2RNHNHSTsOHR 1ORNH(XII)R 2NHSTHERAPEUTIC IMPORTANCEDihydropyrimidines of Biginelli-type have come a long way since theirdiscovery in 1893 and the first patent on DHPM derivatives in 1930, describingagents for the protection of wool against moths 70 .Dihydropyrimidinethiones have attracted considerable attentions as theyappeared of interest to possess wide range of therapeutic activities. Different activitiesare as under.1. Antiviral 71-732. Antimicrobiall 743. Antitumor 75,764. Cardiovascular 775. Antiplasmal 786. Anticarcinogenic 797. Calcium channel modulator 80,818. Antihypertensive 82,839. Vasodialative 8410. Blood platelet aggregation inhibitor 8511. Antiinflammatory 8612. Analgesic 86Thiazolopyrimidines…

Studies on some compounds… 30013. Antilukemic 8714. a1a-Adrenergic receptor antagonist. 88,89Atwal K. et al. 90 synthesized the 3-substituted 1,4-dihydropyrimidine (I)and show that vasorelaxant activity was critically dependent on the size of the C5ester group, isopropyl ester being the best, a variety of substituents (carbamate,acyl, sulfonyl, alkyl) were tolerated at N3. The dihydropyrimidines (I) aresignificantly morepotent than corresponding 2-heteroalkyl-l,4–dihydropyrimidines.Dihydropyridine enantiomers usually show 10-15-fold difference in activity,the enantiomers of dihydropyrimidine (II) show more than a 1000-fold difference inactivity. These results strengthen the requirement of an enamino ester for binding tothe dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.R 2 OOCR 3 PriOOCCOOEtNNH 3 C N SC N SHH(I)(II)Biginelli compound show a diverse range of biological activities. As early as1930 simple derivatives (III) were patented as agent for the protection of wool againstmoths. 91 Later, interest focused on the antiviral activity of Biginelli compounds.92Pyrimidine-5-carboxamides derivatives of type (IV) were reported to possessanticarcinogencic activity, 93 anti-inflammatory, 48,94 analgesic 48, and blood plateletaggregation inhibitory activity. 45H 3NO 2EtOOCClHNHN H 2OHNH(III)H 3 CNHS(IV)H 3 CNHSThiazolopyrimidines…

Studies on some compounds… 301The main interest in Biginelli compounds, however, is due to the strongantihypertensive activity exhibited by certain derivatives. This is not surprising, sincethese dihydropyrimidines can be regarded as aza-analogs of dihydropyridines of thenifedipine type. Dihydropyridines have found widespread use in cardiovascularmedicine and have served as important tools for the study of calcium channelstructure and function. 95Simple modification of the aromatic ring are reported to give substances withonly moderate cardiovascular activity, e.g. (III), 46 (VI), 40 , 96,97 (VII) were shown to bepotent calcium channel blockers, 98-100 but they do not shown any significant antihypertensiveactivity in vivo. 98 This is also the case for bicyclic dihydropyrimidines(V). 101,102NO 2EtOOCC H 3PhNHHNSF 2 HCXEtOOCH 3 CHNHNHSPriOOCH 3 C(V) (VI) (VII)NHNHSCH 3Among the most potent derivatives are Biginelli compounds bearing an estergroup at N-3 (VIII), thereby closely resembling the nifedipine structure.103-106Although the calcium channel blocking activity of these compounds, e.g. (IX), iscomparable to dihydropyridines, most of them are devoid of antihypertensive activityin vivo. 104NO 2NO 2ROOCNCOORPriOOCNCOOEtC H 3NH(VIII)SC H 3NH(IX)SThiazolopyrimidines…

agent. 111 A very recent highlight in this context has been the identification of theStudies on some compounds… 302Atwal K. S. et al. 107 synthesized the 2-[[(4-methoxyphenyl) methyl] thio]-dihydropyrimidines (X) and investigated that pyrimidines are integral parts of suchbiologically important compounds as antiviral, 108,109 antitumor 110 and cardiovascularstructurally rather simple DHPM monastrol (XI) as a novel cell-permeable moleculethat blocks normal bipolar spindle assembly in mammalian cells and therefore causescell cycle arrest. 112 Monastrol specifically inhibits the mitotic kinesin Eg5 motorprotein and can be considered as a new lead for the development of anticancerdrugs. 112,113HOEtOOCH 3 CNH(X)NHSR 2 OOCC H 3NH(XI)NSROut of a library of 16,320 diverse small molecules, Mayer et al. 112 identifiedmonastrol as a lead compound for the development of new anticancer drugs. Byusing an innovative combination of two phenotype- based screens, one based on amitosis-specific posttranslational modification and the other visualizing microtubulesand chromatin, monastrol was recognized as the only cell-permeable compound that iscapable of affecting mitosis in mammalian cells without targeting tubulin.The design, synthesis and screening of libraries of small organic moleculespossessing privileged structures has become a successful strategy in the drugdiscovery process. 114 The term privileged structures is generally used to describe thoseclasses of small organic molecules (

Studies on some compounds… 303compounds. 116The dihydropyrimidine (DHPM) ring represents a heterocyclicstructure of remarkable biological efficiency, as well established through thepharmacological activities exhibited by various DHPM derivatives that have beenidentified as potent calcium channel modulators, orally active antihypertensive agents,antidiabetic and a1a-adrenoreceptor-selective antagonists. 117Incidentally, DHPM derivatives are readily accessible products via theketoester-aldehyde-urea (or thiourea) cyclocondensation known as the Biginelli threecomponent.Reaction. 118Quite recently, the DHPM derivative monastrol (XI) wasdemonstrated to arrest mitosis in mammalian cells by causing the bipolar mitoticspindle to form a monoastral microtubule array surrounded by a ring ofchromosomes. 112 This novel action of monastrol differentiates it from all other knownmitotic inhibitors ranging from colchine to taxol, which instead affect microtubules,the main structural element of the mitotic spindle.Since its discovery in 1999, several papers have appeared in the literaturereporting on the synthesis, 119,120 activity, 121-127 and enantiomeric separation 119,120,128of monastrol and its analogues. 129 Focusing on factors important for bipolar spindleformation, it has been demonstrated that monastrol specifically inhibits in vitro andand in vivo, the motoractivity of the mitotic kinesin Eg5, a motor protein required for112, 123spindle bipolarity.The rapid reversibility of monastrol inhibition activity allows for an exacttemporal control over the cell cycle arrest in mitosis, thus confirming this smallorganic molecule as a new and powerful research probe of cellular processes. 130Furthermore, since compounds that cause mitotic arrest have shown antitumor activityin humans, 130 monastrol may serve as a lead for the development of new anticancerdrugs. A recent study established that, in the case of monastrol, the (S)-enantiomer ismore active than both the (R)-enantiomer and the racemate. 123,124 Both (S)- and (R)-monastrols abolished basal Eg5ATPase activity, with the (S)-enantiomerdemonstrating a 15-fold higher potency. 124Thiazolopyrimidines…

Studies on some compounds… 304HOOEtOH 3 COO+N H 2HH 2 NSYb(OTf) 3HOEtOOCH 3 CNHt-BuMe 2SiOt-BuMe 2 SiClEtOOCNHSH 3 CNHNHSt-BuMe 2SiOt-BuMe 2SiOHPLCEtOOCNHEtOOC+ NHseperationH 3 CNHSH 3 CNHS(R)(S)George C. et al. 131 prepared dihydropyrimidine (XII) was equipotent tonifedipine and amlodipine in vitro. In the spontaneously hypertensive rat,dihydropyrimidine (XII) is both more potent and longer acting than nifedipine andcompares most favorably with the long-acting dihydropyridine derivative amlodipine.Dihydropyrimidine (XII) has the potential advantage of being a single enantiomer.F 3 CPriOOCOH 3 CNNHSON(XII)FThiazolopyrimidines…

Studies on some compounds… 305Edward J. et al. 132 employ difference infrared spectroscopy to probe structuralchanges that occur in the motor protein with monastrol in the presence of either ADPor ATP.Sally Ann P.et al. 133 synthesized 4,6-Bis [(R-carbamoylethyl)thio]-1-phenylpyrazolo[3,4-d] pyrimidine (XIII) was identified as a novel adenosineA1receptor antagonist, antagonizing adenosine-stimulated cyclic adenosine monophosphate generation in guinea pig brain slices. 134,135CH 3N H 2SN H 2CH 3OSNNNNO(XIII)Salvatore B. et al. 136 studied the stopped-flow fluorometry indicates thatmonastrol inhibits ADP release by forming an Eg5-ADP-monastrol ternary complex.Monastrol reversibly inhibits the motility of human Eg5. Monastrol has no inhibitoryeffect on the following members of the kinesin super family: MC5 (Drosophilamelanogaster Ncd), HK379 (H. sapiens conventional kinesin), DKH392 (D.melanogaster conventional kinesin), BimC1-428 (Aspergillus nidulans BimC), Klp15(Caenorhabditis elegans C-terminal motor), or Nkin460GST (Neurospora crassaconventional kinesin).Atwal K. et al. 104 synthesized the 3-substituted 1,4-dihydropyrimidine (XIV)and show that vasorelaxant activity was critically dependent on the size of theC5 ester group, isopropyl ester being the best, a variety of substituents (carbamate,acyl, sulfonyl, alkyl) were tolerated at N3. The dihydropyrimidines (XIV) aresignificantly more potent than corresponding 2-heteroalkyl-l,4-dihydropyrimidines.Dihydropyridine enantiomer usually shows 10-15-fold difference in activity, theenantiomers of dihydropyrimidine (XV) show more than a 1000-fold difference inactivity. These results strengthen the requirement of an enamino ester for binding tothe dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.Thiazolopyrimidines…

Studies on some compounds… 306NO 2rPiOOC(XIV)H 3 CNHNCOOEtSR 2 OOC R 3N(XV)H 3 CNHSAtwal K.S. 98prepared the 2-heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5pyrimidinecarboxylic acid esters which lack the potential C, symmetry ofdihydropyridine calcium channel blockers, were prepared and evaluated for biologicalactivity. Biological assays using potassium-depolarized rabbit aorta and radioligandbinding techniques showed that some of these compounds are potent mimics ofdihydropyridine calcium channel blockers. The combination of a branched ester (e.g.isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal forbiological activity. Dihydropyrimidines (XVI) were found to be 30-fold less active.The solid-state structure of dihydropyrimidine analogue (XVI) shows that thesecompounds can adopt a molecular conformation which is similar to the reportedconformation of dihydropyridine calcium channel blockers.NO 2EtOOCNH 3 C(XVI)NHSThiazolopyrimidines…

Studies on some compounds… 307As a demonstration of this new concept in the Biginelli reaction, the synthesisof two C4 epimer monastrol analogues bearing the ribofuranosyl moiety at C6(XVII), (XVIII), (XIX) has been synthesized by Alessandro D. et al. 137OHOHEtOOCNHEtOOCNHORONHSORONHSOROROROR(XVII)OH(XIX)EtOOCNHOROROORNHS(XVIII)Novel compounds related to 2-(cyclohexylthio)-3,4-dihydro-5-methyl-6-(3-methylbenzyl)-4- oxopyrimidine (XX) ( MC 639) have been synthesized by AntonelloM. et al. 138 and tested as inhibitors of human immunodeficiency virus (HIV-1).OC H 3NHNSC H 3(XX)Thiazolopyrimidines…

Studies on some compounds… 308Numerous classes of non nucleoside reverse transcriptase inhibitors (NNRTIs)have been discovered by Antonello Mai et al. 139 with dihydro-alkyloxy-benzyloxopyrimidines(DABOs) being one of them. The lead compound, an isotrimethoprimderivative (XXI), (XXII), (XXIII) has been synthesized as a possible dihydrofolatereductase inhibitor, and when tested against HIV-1 because of its tructural similaritywith HEPT, 140,141 it was a selective, although not very potent, HIV-1 inhibitor. 142 Onthe basis of these findings, various oxopyrimidines have been synthesized and foundto be specific HIV-1 inhibitors targeted at the reverse transcriptase. 143-146ONHRONHR 1ONHR 1R 2NR 5R 3SR 6NC H 3SNSR 3CH 3R 4(XXI)R 1 = H, MeR 2-4 = Cl, F, NO2R 5 = H, Cl, FR 6 = alkyl,R=H, Me(XXII)R 2R 1-2 = H, MeR 3 = alkyl, cycloalkyl(XXIII)Various 2-thiopyrimidine derivatives have been synthesized by Sondhi S.M.et al. 147 One of the compound, 7,7,8a-trimethyl-hexahydro-thiazolo[3,2-c]pyrimidine-5-thione (XXIV) showed good anti-inflammatory (37.4% at 100mg/kg p.o.) andanalgesic activity (75% at 100mg/kg p.o.). 7-(1-Mercapto-3,3,4a-trimethyl-4,4a,5,9b-tetrahydro-3H-pyrido[4,3-b]indol-7-yl)-3,3,4a-trimethyl-3,4,4a,5-tetrahydro-benzo[4,5] imidazo [1,2-c]pyrimidine-1-thiol (XXV) showed moderate activity againstCDK-1 (IC(50)=5muM). The other compounds showed moderate anti-inflammatory(5-20%), analgesic (25-75%) and protein kinase (CDK-5, GSK-3) inhibitory activities(IC(50)>10muM).Thiazolopyrimidines…

Studies on some compounds… 309SH 3 CC H 3CH 3H 3 CH 3 CHNNCH 3SNHSNHHSNNCH 3CH 3(XXIV)(XXV)NH CH 3Massey A. et al. 148 report that growing human cells extensively incorporate thethiopyrimidine nucleoside 4-thiothymidine (XXVI) (S4TdR) into their DNA. Theincorporated thiopyrimidine (S4T) can also undergo facile S-methylation to 4-thiomethylthymine (S4meT). The rate of methylation of S4TdR in model substrates issimilar to that for the conversion of S6G to S6meG indicating that the DNA of cellsgrown in S4TdR will contain significant levels of S4meT.HNSHNN H 2N(XXVI)NTwenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized byShigeta S. et al. 149 and examined for antiviral activities against herpes simplex virus(HSV), varicella-zoster virus VZV) and human cytomegalovirus (HCMV). In thisstudy, 2'-deoxy-5-alkyl-2-thiocytidine (XXVII) analogues had lower 50% effectiveconcentration (EC50) values against HSV-1, and 2'-deoxy-5-alkyl-2-thiouridine(XXVIII) analogues showed lower.RRO OHH 2 NNONOOHNSOH(XXVII)NHSOH(XXVIII)Thiazolopyrimidines…

Studies on some compounds… 310156New thiopyrimidine derivatives have been synthesized by Bassleer R. et al.Among them, several inhibit the multiplication of Chick embryo cells cultivated invitro they provoke strong nucleoli alterations, prevent the cells from entering intomitosis and can give rise to cell polyploidisation as to DNA.EC50 against VZV than their congeners of arabinoside form. Among thecompounds examined, 2'-deoxy-5-ethyl and 5-propyl-2-thiocytidine (XXIX), (XXX)were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and0.15 microM, and selectivity indexes were more than 7,215 and 1,849, respectively.On the other hand, 2'-deoxy-5-propyl-2-thiouridine, 5-bromovinyl-2-thiouracilarabinoside and 5-styryl-2-thiouracil arabinoside (XXXI)) were most potent andselective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 pM for CaQustrain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities againstthymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosinearabinoside compounds showed marginal anti-CMV activities (EC50s were 57-159pM).C H 3H 3 CO OHH 2 NNN(XXIX)SOHHNOH 2 NNNSO(XXX)OHOHSNH(XXXI)Attia A. M. et al. 150 synthesized N3-beta-D-glucopyranosyl, galactopyranosyland xylopyranosyl 6-methyl-2-methylthiouracil (XXXII) and their 5-bromoderivatives by coupling an a-acetobromosugar with the corresponding thiouracil. Thenew modified thiouridine analogues were evaluated for their inhibitory activityagainst Human Immunodeficiency Virus (HIV) replication in MT-4 cells as well asfor their cytotoxicity.Thiazolopyrimidines…

Studies on some compounds… 311HSH 3 COCNHNOHOOHCH 3OH(XXXII)Twenty 2-thiopyrimidine nucleoside analogues were synthesized by Shigeta S.et al. 151 and examined for inhibitory activity against herpes simplex virus (HSV) type1 and 2, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) andthymidine kinase-deficient HSV (HSV-TK-) replication in vitro.2-thiouracil (thymine) arabinoside, 2'-deoxy-2-thiouridine (XXXIII) and their5-halogenated derivatives showed anti-HSV activity in both RPM18226 (human B-lymphoblastoid cells) and MRC-5 (human embryo lung cells). 2'-Deoxy-5-halogenated-2-thiocytidines (XXXIV) were also inhibitory against HSV, whereas 2-thiocytosine arabinoside and its derivatives were not inhibitory against HSVreplication, except 5-bromo and 5-iodo congeners.ONHNSO OHOH(XXXIII)XO OHH 2 NNNOHS (XXXIV)Massey A. et al. 152 described the thiopurines, 6-thioguanine (XXXV) and 6-mercaptopurine, (XXXVI) are antileukemic agents that are incorporated into DNAfollowing retrieval by the purine salvage pathway.HNSHNNSHHNN H 2N(XXXV)NN N(XXXVI)Thiazolopyrimidines…

Studies on some compounds… 312Their toxicity requires active DNA mismatch repair (MMR) and thiopurineresistance is an acknowledged phenotype of MMR-defective cells. In addition to thesedirect cytotoxic effects, DNA thiobases have distinctive photochemical properties, thetherapeutic potential of which has not been extensively evaluated.Novel D- and L-2'-azido-2',3'-dideoxy-4'-thionucleosides were synthesized byJeong L.S. et al. 153 and evaluated for antiviral activity. When the final nucleosideswere tested against HIV-1, HSV-1, HSV-2 and HCMV they were found to be onlyactive against HCMV without cytotoxicity up to 100 micrograms/ml.154A new thiopyrimidine derivative has been synthesized by Bassleer R. et al.It can inhibit cell multiplication in Chick embryo fibroblasts, in Mouse Ehrlich ascitestumor cells and in Rat hepatoma cells (line Rueber) cultivated in vitro.Transfer RNAs isolated by Kwong L. K. et al. 155 from Escherichia coli Bgrown in the presence of 2-thiouracil are deficient in pseudouridine. Much of thisdeficiency is from the T psi C region, which has only about 50% of its normalpseudouridine content. The other modified nucleoside from this region, ribothymidineis reduced by only about 10%. Studies showed that 2-thiouracil is incorporated intothe RNA of E. coli during growth in the presence of the analog.With an intention of preparing the compounds possessing better therapeuticactivity, we have undertaken the synthesis of dihydropyrimidinthiones which havebeen described in following section.SECTION-7.1:- SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL-5-(3,4–DIMETHYL)-PHENYLAMINOCARBONYL]-6–PHENYL-1,4-DIHYDROPYRIMIDINE-2(1H)-THIONES.Thiazolopyrimidines…

Studies on some compounds… 313INTRODUCTIONBiginelli reaction is not only important to synthesize analogs of DHPM ringusing different building block as potent bioactive heterocycles, but also variousscaffolds can synthesized from this heterocyclic scaffold.Tetrahydro/dihydropyrimidine-2-thiones are the key intermediate for thesynthesis of fused pyrimidines. They have become of considerable interest during thelast forty years 157-169 .Many of these compounds have proved to be active anticancer 161-166 , antipyretic and anti-inflammatory agents, 164-168 calcium antagonist, 169-171analgesic, 172 antitumor, 173-174 antidepresant, 175 antibacterial and antifungal 176-178agents.The parent ring systems of known thiazolopyrimidine derivatives are shown instructures (I-IV).N765S 1 2N4 35H-Thiazolo[3,2-a] pyrimidine(I)1S726 N N4 355H-Thiazolo[3,2-C] pyrimidine(II)N 17S 26 N4356H-Thiazolo[3,4-a] pyrimidine(III)17S 2N N6 45 33H-Thiazolo[3,4-C] pyrimidine(IV)SYNTHETIC ASPECTpyrimidines.The following routs have been employed for the synthesis of thiazoloThiazolopyrimidines…

Studies on some compounds… 314Azole ApproachesStarting from the thiazole ring and subsequent construction of the pyrimidinering in the terminal step.1. Thiazolo [3,2-a]pyrimidine (7) was prepared in 30% yield by the reaction of2-aminothiazole (5) with ethyl cyanoacetate (6) in a sodium ethoxide/ethanolmixture or using polyphosphoric acid 179 or acetic acid. 180-1812. However, oxothiazolopyrimidine (9) was obtained upon treatment withphosphorous pentoxide and methanesulfonic acid (8). 1793. The reaction of (5) with ethyl acetoacetate (10) at 140–150 0 C resulted in theformation of (11) that was then converted to the Z-isomer upon heating at 2500C and cyclized to give (12). 1824. 2-Aminothiazole (5) cyclized with acetyl acetone (13) at 100 0 C, in thepresence of methane sulfonicacid-phosphorus pentoxide or formic acid–phosphorus pentoxide, followed by treatment with 70% perchloric acid, togive the thiazolopyrimidin-4-ium salt (14). 1835. The ester (16) was obtained from 2-aminothiazole (5) with an excess ofmethyl methanetricarboxylate (15) in 61% yield. 1846. Cyclocondensation of (5) with diethyl ethoxymethylene malonate (17) inacetic acid followed by hydrolysis of the ester (18) gave (19). 185-1867. Similarly, 2-aminothiazole (5) reacted with (20) in ethanol to give (21). 1878. Stanovink et al. 188-192 reported the synthesis of a series of thiazolopyrimidinederivatives upon reacting 2-aminothiazole with a variety of different reagents.Thus, dimethylaminobut-2-enoate (or pentenoate), (22), reacted with 5 to givethiazolopyrimidine (23). (Chart 1).9. The reaction of 2-aminothiazole (5) with 2-hydropolyfluoroalk-2-enoate (24) inbasic medium gave two isomers, 7-oxo (25) and its isomeric 5-oxo (26).The structure of both (25) and (26) was established through 1 H NMR, 19FNMR and mass spectra. 19310. 2-Aminothiazole derivatives (5), (R1¼H, CO2Et; R2¼Ph, aryl, Me), reactedwith the acetylenic derivative (27) and ester derivative (28) in ethanol andpolyphosphoric acid, respectively, to give the isomeric oxothiazolopyrimidinederivatives (29) and (30), in 5–32% and 8–97% yield, respectively. 194Thiazolopyrimidines…

Studies on some compounds… 31511. Condensation of 2-aminothiazole (5) in absolute ethanol with the sodium saltof ethyl oximinocyanoacetate (31) gave after acidification (pH 6) with dilutedhydrochloric acid, the nitroso derivative (32) in 92% yield. 19512. Treatment of the 2-aminothiazaole derivatives (5) with the hydrazonederivatives (33) gave the oxothiazolo [3,2-a] pyrimidine derivatives (34). 19613. Compound (37) was prepared in 70–95% yield by thermal (160 0 C)condensation of arylamino bisthiazole (35) with two equivalents of bis (2,4,6-trichlorophenyl) methyl malonate (36). 197 (Chart 2).NCCHCO 2 Et6EtONa/EtOH6/P 2 SCH 3 SO 3 H8MeCOCH 2 COMe10140-150 o CMeCOCH 2 COMe13OH 2 NMeMeO 2 CMeNHNOS7N S9HNNH11MeNNSSR 1. Clo 4R 1 RR=R 1 =HR=R 1 =HRR 1R=R 1 =HRMeH250 o Me NCS MeR 1NMeO 2 C12OR 1R 1 =H 3 COR 1R 114H 2 NNS5CH(CO 2 Me) 315BromobenzeneRNSNR 1 O16OHCO 2 MeR=R 1 =HEtOCO 2 EtCO 2 EtR 1NOCO 2 EtHClR 1NOCOOH17RSNR S N18 19Ar20CO 2 MeCO 2 EtEtOHMeEtOOCNHNN21ARHR 4HN R 4Me 2 NCO 2 R 3R S N R 2R 2N22R 1 23NHOChart-1RR 1R 4R 4Ar =C 6 H 4 O 2 N-mR=R1=HThiazolopyrimidines…

Studies on some compounds… 316R F CF=CHCOa:R F =Cl(CFb:RF=F(CFC:RF=CLCFR 1R 2RfNS N OR 1R 225 26ONS NRClCH 2 C=CCO 2 ME27OClNN29S R 1R 2R 1 =Ph, aryl, MeR 2 =H,CO 2 Et,COMeR 2R 1S5NNH 2ClCH 2 COCH 2 CO 2 Et28N OHClNONS30R 1R 2NCCO 2 EtSNOR 2 NH 231R 132NNOEtO 2 CCOMeNHArNArN=NONCO 2 Et33MeN S34R 2ONArHN S35MeCH(CO 2 C 6 H 2 Cl 3 ) 2N 236Chart-2MeONNAr37SAzine ApproachesStarting from pyrimidine ring and subsequent construction of the thiazole inthe terminal step. Pyrmidinethione derivatives (37-39) were alkylated withmonochloroacetic acid or chloroacetyl chloride and then cyclized to givethiazolopyrimidine derivatives. 198-212 Thus, pyrimidine thione (37) reacted with (40)or (41) in DMF or in an acetic anhydride/ pyridine mixture 200-202 to gave thiazolopyrimidines(42) and (43). Alkylation with (40) in the presence of an aromaticaldehyde 198-200 , 203 , 205-208 , 210 gave the arylidene derivatives (44). Similarly,pyrimidinethione derivatives (38) and (39) reacted with monochloroacetic acid inacetic acid/acetic anhydride/sodium acetate mixture 203-204 or with chloroacetylchloride in dry dioxane to give the corresponding thiazolopyrimidines. (Chart-3)Thiazolopyrimidines…

Studies on some compounds… 317summarizes the pyrimidine-thione derivatives (37-39) used in the synthesis of variousthiazolopyrimidine.OR 1R 2 NH37NHSR 2 R 1R 3NHR 4 N SH38R 1R 2R 3NH39NHSOR 1NHR 237NHSClCH 2 COOHClCH 2 COCl40 4140R 1ONOR 1ONOR 1ONOArR 2NH42SR 2NH43SR 2NH44SThe Hantzsch-type condensation of dihydropyrimidines (39) with a substituted2-bromophenylacetaldehyde (45) led to the thiazolopyrimidine derivatives (46). 213-214R 4R 1 R 1R 2HR 2NHMeCNN+BrR N SR N S3 3HOHR39 45 464Thiazolopyrimidines…

Studies on some compounds… 318Thiazolo[3,2-a]pyrimidine derivatives (48) were prepared by refluxingpyrimidinethione derivative (38) with phenacylbromide (47) in glacial acetic acid. 215-217R 2R 1RR 3O2 R 1NHR 3AcOHBrN+R 4 N S PhHR 4 N38 47 48SPhReaction of pyrimidine thiones (37) with 1,2-dibromoethane (49) gave theoxothiazolopyrimidine derivatives (50) in the presence of DMF/K2CO3 at 70–800C. 218-221OOR 1NHBrCH 2 Br49R 1NR 2K 2 CO 3 /DMFN SR 2 NHH37 50SRetro Diels-Alder reactionBoth azole and azine approaches were considered as major methods forsynthesis of the thiazolopyrimidine. Whereas, the retro Diels-Alder reaction wasconsidered a minor method. Other reported methods include: (i) cyclization ofpropargyl thiopyrimidines in the presence of Pd (II) salts, (ii) metabolism of a N-allylpyrimidine and (iii) reaction of thiazole derivative with isocyanate.THERAPEUTIC IMPORTANCEThiazolo [3,2-a] pyrimidines have generated recent interest due to theirinteresting biological and pharmaceutical activities. Thus, these ring systems havefollowing significant activities.Various derivatives of thiazolo [3,2-a]pyrimidine(I) have been synthesized byB. Tozkoparan et al. 222 and tested for their anti-inflammatory activities at the 100mg/kg dose level compared with indomethacin. Krzysztof Danel and co-workers 223Thiazolopyrimidines…

Studies on some compounds… 319have been synthesized substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-onesand considered as annulated analogues of HEPT. 2,3-Dihydro-5-[(3,5-dimethylphenyl)methyl]-3- ethoxy-6-ethyl-7H-thiazolo[3,2-a]pyrimidin-7-one (II)were found most active against HIV-1.H 3 COOCRNOEtONNSOEtH 3 C(I)SR'C H 3CH 3(II)Antimicrobial activity of thiazolo [3,2-a]pyrimidine (III) and (IV) have beenscreened by H. M. Sayed et al. 224 against various gram positive, gram negativepathogens and fungi.ArArNONONNC 6 H 4 ClArN(III)NSArNN(IV)SR 1Nargues S. Habib, Raafat Soliman, and co-workers 225 have synthesized somethiazolo [4,5-d] pyrimidine (V) derivatives and evaluated for their antimicrobialactivity studies.H 3 C NNRXNSX= O,S(V)R= 2-Br-4-isopropyl- C6H3, 2,4,6- Trimethyl- C6H2R 1=morpholino, N(C 2H 5) 2,NEtBuThiazolopyrimidines…

Studies on some compounds… 320Chun Hu, Huang-quan Lin and co- workers 226 have synthesized 5H-thiazolo[3,2-a]pyrimidine derivatives (VI) and studied their biological activities, they haveevaluated thiazolo pyrimidine compounds as an acetyl cholinesterase inhibitors.HOORC H 3N(VI)NSArThus interesting biological activities of a novel heterocyclic derivative likethiazolopyrimidine have stimulated considerable research work in recent yearsleading to the synthetic utility of the derivatives of this ring system. In our search fornew potential antimicrobial compounds, the reaction series of thiazolopyrimidine withdifferent arylaldehyde under proper conditions has been investigated and thepharmacological profile of the compounds have been studied and described as under.SECTION-7.2: SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-ARYLIDENE-4(4′-METHOXYPHENYL)- 5 - (3,4-DIMETHYLPHENYLAMINO) CARBONYL - 6-PHENYL - 4,7 DIHYDROTHIAZOLO [3,2-α] - PYRIMIDINE 3-ONES.Thiazolopyrimidines…

Studies on some compounds… 321SECTION-7.1SYNTHESIS AND STRUCTURE ELUCIDATION OF 4-ARYL-5-(3,4–DIMETHYL)-PHENYL AMINOCARBONYL] – 6 –PHENYL-1,4-DIHYDROPYRIMIDINE-2(1H)-THIONES.Compounds containing pyrimidine ring are widely distributed in nature. Manyof these derivatives are reported to possess different biological activities. In view ofthese report, we have synthesized pyrimidine derivatives of type- (XIV) by thecondensation of 3,4-dimethyl phenyl) - 3-oxo-3-phenylpropanamide, thiourea and arylaldehydes in presence of catalytic amount of HCl.H 3 CCOH 3NHOThiourea / R-CHOMethanol / HClH 3 CCORCompound-(XIV)H 3NHNHType-(XIV)NHR=ArylSThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (XIVa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (XIVa-j) have been compared with standarddrugs viz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(chapter-8).Thiazolopyrimidines…

Studies on some compounds… 322Reaction SchemeH 3C+H 3CNH 2H 3COOOTolueneRefluxOO+H 3CCH 3NHO+N H 2H 2NSRMethanolHydrochloric acidH 3CCORH 3NHNHNHSType- (XIV)R=ArylThiazolopyrimidines…

Studies on some compounds… 323IR SPECTRAL STUDIES OF 4-[(p-METHOXYPHENYL)-5-(3,4–DIMETHYL)-PHENYL AMINO CARBONYL] –6– PHENYL-1,4-DIHYDRO PYRIMIDINE-2(1H)-THIONES.100.0%T90.080.070.060.050.040.030.020.010.04000.02875.72958.63068.03398.02922.93079.0H 3 CCH 33000.0NH2000.0C H 3OONHHNH1800.0S1274.91375.01338.51386.01607.61530.41472.01600.01575.71400.01200.01015.51100.31157.21169.71402.2 1205.41651.91512.1 1239.21000.0758.0 625.9807.2 610.4470.6669.3 648.0534.2514.0544.9830.3800.0600.0 400.01/cmInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str.(asym.) 2958 2975-2950 227-CH3 C-H str.(sym) 2875 2880-2860 "C-H def.(asym.) 1472 1470-1435 "C-H def.(sym.) 1386 1390-1370 "Aromatic C-H str. 3079 3090-3030 228C=C str. 1512 1540-1480 "Pyrimidine C=C str. 1530 1580-1520 "Moiety C-H str 3068 3090-3030 "C-H i.p. def. 1100 1125-1090 229Amide -NH str 3398 3410-3380 230-NH str 1607 1635-1595 "Carbonyl -C=O str. 1706 1700-1725 "Amide -C=O str. 1651 1690-1660 "Ether C-O-C str 1015 1075-1010 "Thiazolopyrimidines…

Studies on some compounds… 324PMR SPECTRAL STUDIES OF 4-[(p-METHOXYPHENYL)-5-(3,4-DIMETHYL)-PHENYL AMINO CARBONYL]–6–PHENYL- 1,4 –DIHYDROPYRIMIDINE-2(1H)-THIONES.C H 3OH 3 CCH 3NHOHNHNHSInternal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 2.10 6H doublet 2 (CH 3 ) moiety2 3.80 3H Singlet Ar-OCH 33 5.30 1H Singlet -CH (pyrimi.)4 6.91-7.50 12H Multiplet Ar-H5 9.10 1H Singlet -NH (pyrimi.)6 9.62 1H Singlet -NH (pyrimi.)7 10.21 1H Singlet -NH (-NHCO)Thiazolopyrimidines…

Studies on some compounds… 325MASS SPECTRAL STUDIES OF 4-[(p-METHOXYPHENYL)-5-(3,4-DIMETHYL)-PHENYL AMINO CARBONYL]–6 – PHENYL - 1, 4 –DIHYDROPYRIMIDINE-2(1H)-THIONES.H 3COH 3 CH 3 CNHONHNHSm/z = 443.56Thiazolopyrimidines…

Studies on some compounds… 326MASS FRAGMENTATION+H 3 C0OO -+OC H 3ONHNHNHNHSm/z = 267H 3 CO+0m/z = 399C H 3OH C+m/z = 133+0H 3 CCH 3NHONHm/z = 443. 56(M.I.P.)+0NHSNHONHNHm/z = 383+0SONHNHNm/z = 354Thiazolopyrimidines…

Studies on some compounds… 327EXPERIMENTALSYNTHESIS & STRUCTURE ELUCIDATION OF 4-ARYL [5-(3,4–DIMETHYL)–PHENYL AMINOCARBONYL] –6 – PHENYL - 1,4 - DIHYDROPYRIMIDINE -2(1H) –THIONES.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 3,4-DIMETHYL PHENYL) – 3 –OXO – 3 – PHENYLPROPANAMIDE.Pls. refer chapter no. 6- Section -6.1:- page no.-260[B] PREPARATION OF 4 –[(p-METHOXYPHENYL)-5 - (3,4 – DIMETHYL)–PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 -DIHYDROPYRIMIDI NE -2(1H) –THIONES.A mixture of thiourea (1.2gm, 0.015mole), 4-methoxy benzaldehyde (1.5gm,0.01mole) and N-(3,4-dimethylphenyl)-3-oxo-3-phenylpropanamide (2.67gm, 0.01mole) in 15 ml of ethanol containing few drops of concentrated hydrochloric acid wasrefluxed for 8 hrs. The solution was allowed to stand for 12 hrs. at room temperatureand the resulting solid mass separated was filtered and crystallized from dioxane.Yield 67%, m.p.265˚C, [C 26 H 25 N 3 O 2 S; required C, 70.40, H, 5.68, N, 9.47 % found:C, 70.43, H, 5.62, N, 9.42 %].Similarly, other 4 - aryl [5 - (3,4 – dimethyl) – phenyl amino carbonyl] – 6 –phenyl- 1,4 - dihydropyrimidine -2(1H) –thiones were prepared. The physical data arerecorded in Table No.14.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8).Thiazolopyrimidines…

Studies on some compounds… 328[C] BIOLOGICAL EVALUATION OF 4 -ARYL [5 -(3,4 – DIMETHYL) –PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 - DIHYDROPYRIMIDINE -2(1H) –THIONESAntimicrobial testing were carried out as described in Chapter-8.The zones ofinhibition of test solutions are recorded in Graphical Chart-14a, Table-14a. PageNo.-396, 397. Result and discussion is given on table no.: - 398.Thiazolopyrimidines…

Studies on some compounds… 329● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Thiazolopyrimidines…

Studies on some compounds… 330SECTION-7.2SYNTHESIS AND STRUCTURE ELUCIDATION OF 2-ARYLIDENE -N-(3,4-METHYLPHENYL)-3,5-DIHYDRO-7-METHYL-3-OXO-5- PHENYL -2H-THIAZOLO [3,2-a] PYRIMIDINE - 6 -CARBOXAMIDES.Compounds containing pyrimidine ring are widely distributed in nature. Manyof these derivatives are reported to possess different biological activities. In view ofthese report, we have synthesized 2-arylidene -N-(3,4-dimethylphenyl)-3,5-dihydro-7-methyl-3-oxo-5- phenyl -2H-thiazolo [3,2-a] pyrimidine - 6 –carboxamides of Type-(XIII) by the condensation 1,2,3,4 tetrahydro - 4-(4-metrhoxy phenyl )-N-(3,4-dimethyl phenyl )-6-phenyl -2- thioxo pyrimidine -5-carboxamide and differentaromatic aldehyde.C H 3OH 3 CH 3 CNHONHNHSClCH 2 COOHR-CHOH 3 COCompound-(XV)Type-(XV)H 3 CH 3 CNHONNSORThe structure elucidation of the synthesized compounds has beencharacterized by using elemental analysis, infrared and 1 H-Nuclear magneticresonance spectroscopy and further supported by Mass spectrophotometry.All the purified organic compounds (XVa-j) have been screened for their invitro therapeutic assay like Antibacterial activities towards Gram positive andGram negative bacterial strain and Antifungal activities towards fungal strains atdifferent concentrations (Minimum Inhibitory Concentration). The biologicalactivities of synthesized compounds (XVa-j) have been compared with standard drugsviz. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin(antibacterial) Nystatin, and Greseofulvin (antifungal) at different concentrations(Chapter-8).Thiazolopyrimidines…

Studies on some compounds… 331Reaction SchemeC H 3OH 3 CCH 3NHOO+HNH 2SH 5 C 6OH 2 NH +EthanolC H 3OH 3 CH 3 CNHONHH 5 C 6NHSClCH 2 COOHCH 3 COONa(CH 3 CO) 2 O/CH 3 COOHR-CHOC H 3OH 3 CH 3 CNHONOType- (XV)H 5 C 6NHSR=arylRThiazolopyrimidines…

Studies on some compounds… 332IR SPECTRAL STUDIES OF 2-(p-METHOXYPHENYL)-4-(4’-METHOXYPHENYL) – N - (3,4-DI METHYLPHENYL) - 3,5 – DIHYDRO – 7 - METHYL– 3 – OXO - 5-PHENYL-2H -THIAZOLO [3,2-a]PYRIMIDINE - 6 –CARBOXAMIDE.H 3O CH 3COH 3 CCOOH 3NHNNSInstrument: SHIMADZU- FT-IR -8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration mode Frequency in cm-1 Ref.Observed ReportedAlkane C-H str. (asym.) 2967 2975-2950 227-CH3 C-H str. (sym) 2831 2880-2860 "C-H def. (asym.) 1457 1470-1435 "C-H def.(sym.) 1375 1390-1370 "Aromatic C-H str. 3082 3090-3030 228C=C str. 1536 1540-1480 "C-H i.p. def. 1024 1070-1000 "C-H o.o.p. def. 834 835-810 "Thiazolo C=C str. 1553 1580-1520 229pyrimidine C-H str. 3082 3080-3030 "moiety C-H i.p. def. 1112 1125-1090 "C-H o.o.p. def. 834 900-650 "Amine -NH str. 3302 3410-3380 230C-N str. 1327 1360-1310 "Carbonyl -C=O str. 1673 1700-1725 "Amide -C=O str. 1660 1690-1660 "Ether C-O-C str. 1000 1000-950 "Thiazolopyrimidines…

Studies on some compounds… 333PMR SPECTRAL STUDIES OF 2-(3,4-DIMETHOXYPHENYL)-4(4’-METHOXY PHENYL) – N - (3,4-DI METHYLPHENYL) - 3,5 – DIHYDRO – 7- METHYL – 3 – OXO - 5-PHENYL-2H -THIAZOLO [3,2-a]PYRIMIDINE - 6–CARBOXAMIDE.COH 3 CCOHH 3O CH 3OH 3NHNHNSOCH 3Internal Standard: TMS; Solvent: DMSO: Instrument: BRUKER Spectrometer (300MHz).Signalno.Signal position(δppm)Relative No.of protonsMultiplicityInference1 2.18 6H doublet 2 (CH 3 ) moiety2 3.72 3H Singlet Ar-OCH 33 3.82 6H doublet 2(OCH 3 )3 6.25 1H Singlet -CH (pyrimi.)4 6.81-7.78 15H Multiplet Ar-H5 7.85 1H Singlet -NH (-NHCO)6 9.62 1H Singlet -CH (Vinyl)Thiazolopyrimidines…

Studies on some compounds… 334MASS SPECTRAL STUDIES OF 2-(3,4-DIMETHOXYPHENYL)-4(4’-METHOXYPHENYL) – N - (3,4-DI METHYLPHENYL) - 3,5 – DIHYDRO – 7 -METHYL – 3 – OXO - 5-PHENYL-2H -THIAZOLO [3,2-a]PYRIMIDINE - 6 –CARBOXAMIDE.C H 3OH 3 CH 3 CNHONONSm/z = 631.74OO CH 3CH 3Thiazolopyrimidines…

Studies on some compounds… 335MASS FRAGMENTATIONCOH 3 CH 3 CNHC H 3OONNOHSH+H 3 CCH 3NNHONHH 3m/z = 445NHSH+0+0C H 3NHOm/z = 239H 3 COOONHNNSCH + .m/z = 4850NSm/z = 112H 3 CCH 3NHOCH +CHNCSH 3 CCO+0+m/z = 309NHNH 3m/z = 379NOCH 3m/z = 603(M.I. P.)O CH 3NH+N0m/z = 158(B. P.)H 3 CCO+0ONHNHCH 3m/z = 370NHNHH 3+NH0NHm/z = 384Thiazolopyrimidines…

Studies on some compounds… 336EXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 2-ARYLIDENE -N-(3,4-METHYLPHENYL)-3,5-DIHYDRO-7-METHYL-3-OXO -5- PHENYL -2H-THIAZOLO [3,2-a] PYRIMIDINE - 6 -CARBOXAMIDES.Melting points of all the synthesized compounds were taken in open capillarysystem. The purification of all the compounds was carried out by crystallization inappropriate solvents. TLC was carried out on silica gel-G as stationary phase.[A] PREPARATION OF 4 - METHOXYPHENYL [5 - (3,4 – DIMETHYL) –PHENYL AMINO CARBONYL] – 6 – PHENYL - 1,4 - DIHYDROPYRIMIDINE -2(1H) –THIONES.Pls. refer Chapter No.-7, Section:- 7.1, Page No.-327[B] PREPARATION OF 2-(3,4-DIMETHOXYHENYL)–N-(3,4-METHYLPHENYL) -3,5-DIHYDRO – 7 - METHYL -3- OXO – 5 - PHENYL -2H-THIAZOLO-[3,2-a] PYRIMIDINE - 6 -CARBOXAMIDES.A mixture of 4 - methoxyphenyl [5-(3,4 – dimethyl) – phenyl amino carbonyl] –6– phenyl-1,4-dihydropyrimidine-2(1H)–thiones (6 gm, 0.01 mole), monochloroacetic acid (1.41 gm, 0.015 mole), anhydrous sodium acetate (2 gm), glacial aceticacid (20 ml), acetic anhydride (15 ml) and 4-methoxybenzaldehyde (1.36 gm, 0.01mole) were heated to reflux for 3-4 hr. The reaction mixture was cooled to roomtemperature and poured on to crushed ice with vigorous stirring. The precipitatedsolid was filtered under suction, washed with cold water and isolate the product.Yield- 52%, m. p.- 212 0 C; (C 36 H 31 N 3 O 4 S; required: C, 71.86; H, 5.19; N, 6.98 %;found: C, 71.81; H, 5.23; N, 6.96 %).Similarly, other 2-arylidene -N-(3,4-dimethylphenyl)-3,5-dihydro-7-methyl-3-oxo-5- phenyl -2H-thiazolo [3,2-a] pyrimidine - 6 –carboxamide were prepared. Thephysical constants are recorded in Table-15.TLC System: For [A] and [B]: Ethyl Acetate: Ethylene dichloride (2:8).Thiazolopyrimidines…

Studies on some compounds… 337[C] BIOLOGICAL EVALUATION OF 2-ARYLIDENE –N- (3,4-METHYLPHENYL)-3,5-DIHYDRO-7- ETHYL-3-OXO-5- PHENYL -2H-THIAZOLO [3,2- a] PYRIMIDINE - 6 -CARBOXAMIDES.Antimicrobial testing were carried out as described in Chapter-8.The zones ofinhibition of test solutions are recorded in Graphical Chart-15a, Table-15a. Page-No.-399, 400. Result and discussion is given on page no.:- 401.Thiazolopyrimidines…

Studies on some compounds… 338● S1= Ethylene dichloride: Ethyl acetate (8:2), S2 = Toluene: Ethyl acetate (8:2)Thiazolopyrimidines…

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Studies on some compounds… 346106. Cho H.; Ueda M.; ShimaK.; Mizuno A.; Hayashimatsu M.; Ohanaka Y.;Takeuchi Y.; Hamaguchi M.; Aisaka K.; Hidaka T.; Kawai M.; Takeda M.;Ishihara T.; Funahashi K. J. Med. Chem 32, 2399 (1989).107. Karnail S. Atwal ;George C. Rovnyak; Brian C. O’Reilly; Joseph Schwartz.J.Org. Chem. 54, 5898 (1989).108. Hull R.; Swain G.British Patent. 868030 (1961).109. McKin-stry D.; Reading E. H.J. Franklin Inst. 237, 203 (1944).110. Hurst E. W.; Hull R.J. Med. Pharm. Chem. 3, 215 (1961).111. Khania E. L.; Sillinietse G.; Dabur, G. Ya.; Kimenis A. A.Khim. Pharm. Zh. 78, 1321 (1978).112. Mayer T. U.; Kapoor T. M.; Haggarty S. J.; King R. W.; Schreiber S. L.;Mitchison T.J. Science. 286, 971 (1999).113. Haggarty S. J.; Mayer T. U.; Miyamoto D. T.; Fathi R.; King R. W.;Mitchison T. J.; Chem. Biol. 7, 275 (2000).114. Lebl M.J. Comb. Chem. 1, 3-24 (1999).115. Thompson L. A.; Ellman J. A.Chem. Rev. 96, 555-600 (1996).116. Fox S.; Farr-Jones S.; Yund M. A.J. Biomol. Screening. 4, 183-186 (1999).117. Kappe C. O.Eur. J. Med. Chem. 35, 1043-1052 (2000).118. Kappe C. O.Acc. Chem. Res. 33, 879-888 (2000).119 Dondoni A.; Massi A.; Sabbatini S.Tetrahedron Lett. 43, 5913-5916 (2000).120. Kappe C. O.; Shishkin O. V.; Uray G.; Verdino P.Tetrahedron. 56, 1859-862(2000).121. Khodjakov A.; Copenagle L.; Gordon M. B.; Compton D. A.; Kapoor T. M.J. Cell. Biol. 160, 671-683(2000).Thiazolopyrimidines…

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Studies on some compounds… 348136. Salvatore DeBonis, Jean-Pierre Simorre, Isabelle Crevel, Luc Lebeau,Dimitrios A.Skoufias, Anne Blangy, Christine Ebel, Pierre Gans, RobertCross, David D. Hackney, Biochemistry. 42, 338-349 (2003).137. Alessandro Dondoni, Alessandro Massi, Simona Sabbatini, Valerio Bertolasi.J. Org. Chem. 67, 6979-6994 (2002).138. Antonello Mai, Marino Artico, Gianluca Sbardella, Silvana Quartarone, SilvioMassa, Anna G. Loi, Antonella De Montis, Franca Scintu, MonicaPutzolu,Paolo La Colla.J. Med. Chem. 40, 1447-1454 (1997).139. Antonello Mai, Marino Artico, Gianluca Sbardella, Silvio Massa, EttoreNovellino, Giovanni Greco, Anna Giulia Loi, Enzo Tramontano, Maria ElenaMarongiu, Paolo LaColla.J. Med. Chem. 42, 619-627 (1999).140. Tanaka H.; Baba M.; Hayakawa H.; Sakamaki T.; Miyasaka T.; Ubasawa M.;Takashima H.; Sekiya K.; Nitta I.; Shigeta S.; Walker R. T.; Balzarini J.; DeClercq. E.J. Med. Chem. 34, 349-357 (1991).141. Baba M.; Shigeta S.; Tanaka H.; Miyasaka T.; Ubasawa M.; Umezu K.;Walker R. T.; Pauwels R.; De Clercq E.Antiviral Res. 17, 245-264 (1992).142. Botta M.; Artico M.; Massa S.; Gambacorta A.; Marongiu M. E.; Pani A.; LaColla P.Eur. J. Med. Chem. 27, 251-257 (1992).143. Artico M.; Massa S.; Mai A.; Marongiu M. E.; Piras G.; Tramontano E.; LaColla P.Antiviral Chem. Chemother. 4, 361-368 (1993).144. Tramontano E.; Marongiu M. E.; De Montis A.; Loi A. G.; Artico M.; MassaS.; Mai A.;La Colla P.Microbiologica. 17, 269-279 (1994).145. Massa S.; Mai A.; Artico M.; Sbardella G.; Tramontano E.; Loi A. G.; ScanoP.; La Colla. Antiviral Chem. Chemother. 6, 1-8 (1995).146. Mai A.; Artico M.; Sbardella G.; Massa S.; Loi A. G.; Tramontano E.; ScanoP.; La Colla P.J. Med. Chem. 38, 3258-3263 (1995).147. Sondhi S. M.; Goyal R. N.; Lahoti A. M.; Singh N.; Shukla R.; Raghubir R.Bioorg. Med. Chem. 9, 3185 (2005).Thiazolopyrimidines…

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Studies on some compounds… 350163. Y. Masisumi; Japanese Patent, 7, 982 (62);Chem. Abstr., 59, 8764 (1963).164. A. Takamizawa, Y. Hamashima;Japanese Patent, 14, 423 (66); Chem. Abstr., 65, 201,44b (1966).165. A. Takamizawa, Y. Hamashima;Japanese Patent, 17, 595 (65); Chem. Abstr., 63, 19112h (1965).166. Ito, Japan, 7030, 101 (1970);Chem. Abstr., 74, 22827e (1971).167. V. Sprio, S. Plescia;J. Heterocyclic Chem., 9, 951 (1972).168. A. Takamizawa, H. Sato,Japanese Patent, 72, 45,595 (1972); Chem. Abstr., 78, 58454c (1973).169. A. Balkan, M. Ertan, T. Burgemeister;Arch. Pharm., (Weinheim), 325, 499 (1992).170. A. Balkan, S. Uma, M. Ertan W. Wiegrebe;Pharmazie, 47, 687 (1992).171. A. Balkan, B. Tozkoparan, M. Ertan, Y. Sara, N. Ertekin;Boll. Chim. Farm., 135, 648 (1996).172. J. Baetz; Brit., 1,334,628 (1973);Chem. Abstr., 80, 48028u (1974).173. B. Dash, M. Patra, P. K. Mohapatra;J. Inst. Chem., 52, 92 (1980); Chem. Abstr., 93, 239353z (1980).174. Teijin Ltd.;Jpn. Kokai Tokkyo Koho JP, 58, 24,590 [83, 24,590] (1983); Chem. Abstr., 98,215611j (1983).175. D. Bigg (Synthelabo S.A.);Fr. Demande FR, 2, 479, 831 (1981); Chem. Abstr., 96, 162725z, (1982).176. J. Mohan, V. K. Chadha, H. S. Chaudhary, B.D. Sharma, H. K. Pujari;Indian J. Exp. Biol.,10, 37 (1972).177. S. N. Dehuri, A. Nayak;J. Ind. Chem. Soc., 60, 970 (1983).178. H. R. Champaneri, S. R. Modi, H. B. Naik; Asian J. Chem., 6, 737 (1994);Chem. Abstr., 121, 300842y (1994).179. T. Tsuji;Thiazolopyrimidines…

Studies on some compounds… 351J. Heterocycl. Chem., 28, 489 (1991).180. M. A. Jacobson, R. Norton;PCT Int. Appl. WO 97 33, 879 (1997); Chem. Abstr., 127, 293241v (1997).181. M. M. El-kerdawy, M. A. Moustafa, L. M. Gad, S. M. E. Badr;Bull Fac. Pharm. (CairoUniv.), 31(1), 67 (1993); Chem. Abstr., 121, 57472b(1994).182. S. Sharma, M. S. Khanna, C. P. Garg, R. P. Kapoor, A. Kapil, S. Sharma;Indian J. Chem. Sec.B, 32B(6), 693 (1993).183. K. Takenaka, T. Tsuji;J. Heterocycl. Chem., 33, 1367 (1996).184. A. Kutyrevand, T. Kappe;J. Heterocycl. Chem., 36, 237 (1999).185. D. R. Shridhar, M. Jogibhukta, V. S. Krishnan;Indian J. Chem. Sec. B, 25B(3), 345 (1986).186. T. Shioiri, K. Ninomija, S. Yamada;J. Am. Chem. Soc., 94, 6203 (1972).187. T. Mishina, N. Tsuda, A. Inui, Y. Miura;Jpn. Kokai Tokkyo Koho JP 62, 169, 793; (1987); Chem. Abstr. 108, 56120e(1988).188. L. Selic, S. G. Grdadolnik, B. Stanovnik;Heterocycles, 45(12), 2349 (1997).189. G. Sorsak, S. G. Grdadolnik, B. Stanovnik;J. Heterocycl. Chem., 35, 1275 (1998).190. L. Selic, B. Stanovnik;J. Heterocycl. Chem., 34, 813 (1997).191. G. Sorsak, A. Sinur, L. Golic, B. Stanovnik;J. Heterocycl. Chem., 32, 921 (1995).192. B. Stanovnik, H. Van de Bovenkamp, J. Svete, A. Hvala, I. Simonic, M.Tisher;J. Heterocycl.Chem., 27, 359 (1990).193. Y. S. Liu, W. Y. Huang;J. Chem. Soc. Perkin Trans., 1(6), 981 (1997).194. D. Janietz, B. Goldmann, W. D. Rudorf ;J. Prakt. Chem., 330(4), 607 (1988).Thiazolopyrimidines…

Studies on some compounds… 352195. M. R. D. Giudice, A. Borioni, C. Mustazza, F. Gatta, B. Stanovnik;J.Heterocycl. Chem., 32, 1725 (1995).196. M. A. Metwally, A. M. Ismaiel, Y. M. Yousif, F. Eid;J. Indian Chem. Soc., 66(3), 179 (1989).197. G. O. Mbagwa, R. Garland;J. Heterocycl. Chem., 25, 571 (1988).198. S. A. Abdel-Aziz;Phosphorus, Sulfur Silicon Relat. Elem., 116, 39 (1996).199. F. M. Manhi, A. M. Abdel-Fattah;Egypt. J. Pharm., 33(5–6), 825 (1992); Chem. Abstr., 121, 83254b (1994).200. J. M. Parmar, A. R. Parikh;Heterocycl. Commun., 4(5), 463 (1998).201. M. Ghorab, Y. A. Mohamed, S. A. Mohamed, Y.A. Ammar;Phosphorus, Sulfur Silicon Relat.Elem., 108(1–4), 249 (1996).202. K. M. Ghoneim, M. Y. H. Essawi, M. S. Mohamed, A. M. Kamal;Pol. J. Chem., 72(7), 1173 (1998).203. M. R. Mohamoud, A. Y. Soliman, H. M. Bakeer;Indian J. Chem. Sec. B, 29B(9), 830 (1990).204. H. R. Champaneri, S. R. Modi, H. B. Naik;Asian J. Chem., 6(3), 737 (1994); Chem. Abstr.,121, 300842y (1994).205. H. Y. Moustafa;Indian J. Heterocycl. Chem., 7(4), 273 (1998).206. M. A. Salama, H. H. Mousa, M. Al-Shaikh;Orient. J. Chem., 7(4), 185 (1991); Chem. Abstr.,116, 151713z (1992).207. M. A. F. Sharaf, F. A. Abdel Aal, A. M. Abdel Fattah, A. M. R. Khalik;J. Chem. Res. (S), 354 (1996).208. B. Tozkoparan, M. Ertan, P. Kelicen , R. Demirdamar;Farmaco, 54(9), 588 (1999).209. M. S. Akhtar, M. Seth, A. P. Bhaduri;Indian J. Chem. Sec. B, 26B(6), 556 (1987).210. M. A. Salama, H. H. A Mousa, S. A. El-Essa;Orient. J. Chem., 7(3), 128 (1991); Chem. Abstr., 116, 41405t (1992).211. R. M. Abdel-Rahman, M. Fawzy, I. El-Baz;Pharmazie, 49, 729 (1994).Thiazolopyrimidines…

Studies on some compounds… 353212. C. D. Kappe, P. Roschger;J. Heterocycl. Chem., 26, 55 (1989).213. G. Adam, S. Kolczewski, V. Mutel, J. Wichmann;Eur. Pat. Appl. Ep 891,978, (1999); Chem. Abstr., 130, 125087t (1999).214. J. Wichmann, G. Adam, S. Kolczewski, V. Mutel, T. Woltering; Bioorg. andMedi. Chem. Lett., 9, 1573 (1999).215. A. Balkan, S. Uma, M. Ertan, W. Wiegrebe;Pharmazie, 47(9), 687 (1992).216. A. Balkan, M. Ertan, T. Burgemeister;Arch. Pharm. (Weinheim, Ger.), 325(8), 499 (1992).217. S. A. Abdel-Aziz, H. A. Allimony, H. M. El-Shaaer, U. F. Ali, R. M. Abdel-Rahman; Phosphorus,Sulfur Silicon Relat. Elem., 113, 67 (1996).218. V. J. Ran, A. Goel, M. Nath, P. Srivastava;Bioorg. and Med. Chem. Lett., 4(22), 2653 (1994).219. V. J. Ram;Arch. Pharm. (Weinheim, Ger.), 324(11), 837 (1991).220. A. Mobinikhaledi, N. Foroughifar, F. Goodarzi;Phosphorus, Sulfur Silicon Relat. Elem., 179, 507-512 (2004).221. A. Mobinikhaledi, N. Foroughifar, B. Ahamadi;Phosphorus, Sulfur Silicon Relat. Elem., 180, 339-345 (2005).222. B. Tozkoparan, M. Ertan, P. Kelicen, R. Demirdamar;Il Farmaco, 54, 588–593 (1999).223. K. Danel, E. B. Pedersen, C. Nielsen;J. Med. Chem., 41, 191-198 (1998).224. H. H. Sayed, A. H. Shamroukh, A. E. Rashad;Acta Pharm., 56, 231–244 (2006)225. Nargues S. Habib, Raafat Soliman, Alaa A. El-Tombary, Soad A. El-Hawash,and Omaima G. Shaaban;Arch Pharm Res Vol 30, No 12, 1511-1520,(2007).226. Hui Zhi, Lan-mei Chen, Lin-lin Zhang, Si-jie Liu, David Chi Cheong Wan,Huang-quan Lin,and Chun Hu;ARKIVOC. (XIII), 266-267, 2008.227. V. M. Parikh; “Absorption spectroscopy of organic molecule” Additionweslay Pub. Co. London, 243, 258 (1978).Thiazolopyrimidines…

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CHAPTER - 8STUDIES ON BIOLOGICALACTIVITY STUDIES

Studies on some compounds… 355[A]ANTIMICROBIAL ACTIVITY STUDIESThe antimicrobial activities of new synthesized compounds were determinedusing Broth dilution method. The standard strains used for the activity were procuredfrom Institute of Microbial Technology, Chandigarh.In this method each synthesized drug was diluted obtaining 2000microgram/ml concentration, as a stock solution. The 10 µL suspensions from eachwell was further inoculated on appropriate media and growth was noted after 24 and48 hrs at 37˚C. The lowest concentration, which showed no growth after spotsubculture was considered as MBC / MFC for each drug. The result of this test isaffected by the size of inoculums. The test mixture should contain 10 8 organism/ml.In this method the results are recorded in the form of primary and secondaryscreening.Primary screening: In primary screening 1000ug/ml, 500ug/ ml, 250 ug/ml, and 125ug/ml concentrations of the synthesized drugs were taken. The synthesized drugsfound to be active in this primary screening were further tested in second set ofdilution against all microorganisms.Secondary screening: The drugs found active in primary screening were similarlydiluted to obtain 100 ug/ml, 50 ug/ml, 25 ug/ml, 12.5 ug/ml, 6.250 ug/ml, 3.125 ug/mland 1.5625 ug/ml concentrations.Antibacterial activity: In vitro antibacterial activity of the compounds was carriedout against culture of Escherichia coli, Pseudomonas aeruginosa, Staphylococcusaureus and S.pyogenus at concentrations of 1000, 500, 200, 100, 50, 25, 12.5 µg/mlrespectively. The drugs Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin,Norfloxacin were used as a standard for antibacterial activity at differentconcentration, which is described in Graphical chart no: 1-15 and 1a-15a.Antifungal activity: In vitro antifungal activity of same synthesized compounds wastested against C.albicans, Aspergillus’s niger and A.clavatus. The compounds weretested at different concentrations of 1000,500,200,100 µg/ml respectively, in whichNystatin, Greseofulvin used for antifungal activity, at different concentration which isdescribed in Graphical chart: 1a-15a and 1a-15a.Biological activity…

Studies on some compounds… 356ANTIMICROBIAL ACTIVITYMethod : Broth Dilution MethodGram positive bacteria : Staphylococcus pyogenesStreptococcus aureusGram negative bacteria : Escherichia coli: Pseudomonas aeruginosaFungi : Candida albicans: Aspergillus Niger: Aspergillus clavatusConcentrations for M.I.C. : 1000 µg/ml, 500 µg/ml,250 µg/ml, 125 µg/ml,62.5 µg/ml, 50 µg/ml.Solvent : DMFStandard drugs : Gentamycin, Ampicillin,Chloramphenicol,Ciprofloxacin,Norfloxacin,Nystatin, Greseofulvin.The antibacterial activity of synthesized compounds was compared withstandard drugs viz., Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin andNorfloxacin. Antifungal activity was compared with Nystatin and Greseofulvin.Biological activity…

Studies on some compounds… 357TABLE-1a:- ANTIMICROBIAL ACTIVITY OF 4-ISOPROPOXY-N'-[(1E)-(ARYL) METHYLENE] BENZOHYDRAZIDE.Biological activity…

Studies on some compounds… 358GRAPHICAL CHART-1a:- ANTIMICROBIAL ACTIVITY OF 4-ISOPROPOXY-N'-[(1E)-(ARYL) METHYLENE]BENZOHYDRAZIDE.Biological activity…

Studies on some compounds… 359RESULTS AND DISCUSSION:OOH 3 CNH NCH 3RANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type (I)were found to be mild to moderately active against Gram positive and Gram negativebacterial strains.The maximum activity was observed in compounds bearing R=m-phenoxyphenyl, N,N,-dimethylphenyl substituents against E.coli. and P. aeruginosa, incomparision to standard drug Ampicillin. However the compounds beaing 2-thiophene, 5-nitro vanilline substitutes is also giving maximum activity against S.pyogenus.The significant activity was displayed by the compounds bearing R=N,Ndimethylphenyl against S.aureus in comparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= m-nitro phenyl, m-phenoxy phenyl, N, N-dimethyl phenyl, dimethoxy phenyl indicate significant activity in comparision toGreseofulvin against C.albicans.Biological activity…

Studies on some compounds… 360TABLE - 2a:- ANTIMICROBIAL ACTIVITY OF 2-(4-ISOPROPOXYPHENYL)-5-(ARYL)-1, 3, 4-OXADIAZOLE.Biological activity…

Studies on some compounds… 361GRAPHICAL CHART - 2a:- ANTIMICROBIAL ACTIVITY OF 2-(4-ISOPROPOXYPHENYL)-5-(ARYL)-1, 3, 4-OXADIAZOLE.Biological activity…

Studies on some compounds… 362RESULTS AND DISCUSSION:N NOH 3 CORCH 3ANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds oftype (II) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= 2-thiophenesubstituent against E.coli. and P. aeruginosa in comparision to standard drugAmpicillin. However the compounds bearing R = p-hydroxy and N-N dimethylphenyl substituent are also giving maximum activity againstP. aeruginosa.The significant activity was displayed by the compounds bearing R= p-methoxy phenyl and 3,4-dimethoxy phenyl against S. aureus and S. pyogenus incomparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-methoxy phenyl, 3-methoxy-4-hydroxyphenyl indicate significant activity to Greseofulvin against C.albicans.While compounds bearing R= m-nitro phenyl substitute is giving significant activityagainst A.niger in comparision to Greseofulvin and Nystatin.Biological activity…

Studies on some compounds… 363TABLE - 3a:- ANTIMICROBIAL ACTIVITY OF 2-(4-ISOPROPOXYPHENYL)-3-N-(ARYL) AMINOMETHYL - 1, 3, 4 OXADIAZOLE -5 (4H) –THIONE.Biological activity…

Studies on some compounds… 364GRAPHICAL CHART-3a:- ANTIMICROBIAL ACTIVITY OF 2-(4-ISOPROPOXYPHENYL)-3-N-(ARYL)AMINO METHYL - 1, 3, 4 OXADIAZOLE -5 (4H) –THIONE.Biological activity…

Studies on some compounds… 365RESULTS AND DISCUSSION:N NOH 3 COSCH 3RNHANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds oftype (III) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R=m-Methoxyphenyl, m-nitro phenyl substituent and R = 3,4-dimethyl phenyl, m-chloro phenylagainst E.coli. and P. aeruginosa respectively, in comparision to standard drugAmpicillin. However The compounds beaing p-methoxy phenyl, methyl phenyl andm-chloro phenyl substitutes are also giving maximum activity against. S. pyogenus.In comparision to standard drug Ampicillin.The significant activity was displayed by the compounds bearing R=m-chlorophenyl and p-methyl phenyl against S.aureus in comparision to standard drugAmpicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-methoxy phenyl, m-nitro phenylindicate maximum activity in comparision to Nystatin and significant activity incomparision to Greseofulvin against C.albicans. while compounds bearing R= p-methylphenyl substitue is giving significant activity against A. niger in comparisionto Nystatin and Greseofulvin.Biological activity…

Studies on some compounds… 366TABLE - 4a:- ANTIMICROBIAL ACTIVITY OF 2,3-DICHLORO N-(3-SUBSTITUTED STYRYL CARBONYL)BENZAMIDE.Biological activity…

Studies on some compounds… 367GRAPHICAL CHART-4a:- ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO N-(3-SUBSTITUTEDSTYRYL CARBONYL) BENZAMIDEBiological activity…

Studies on some compounds… 368RESULTS AND DISCUSSION:ClClORONHANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds oftype (IV) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= phenyl, 2-thiophene, m-phenoxy phenyl, 4-hydroxy-3-methoxy phenyl substituents againstE.coli. and P. aeruginosa in comparision to standard drug Ampicillin. However thecompounds beaing p-methoxy substitute is also giving maximum activity against S.aureus.The significant activity was displayed by the compounds bearing R=pmethoxyphenyl against E.coli. and R= 3,4dimethoxy phenyl against S.pyogenus incomparision to standard drug Ampicillin.Where, compound bearing 3,4-dmethoxy phenyl substitute is indicatingcomparable activity against E.coli and significant activity against P. aeruginosa incomparision to standard drug Chloramphenicol.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= 3,4-dimethoxy phenyl, m-phenoxy phenyland m-nitro phenyl substitutes indicate maximum activity in comparision toNystatin and significant activity in comparision to Greseofulvin against C.albicans.While compounds bearing R= nitro phenyl, 4-hydroxy 3-methoxy phenyl substitutesare also giving maximum activity against A.niger and m-phenoxy phenyl, halosubstituted are showing maximum activity against A. Clavatus in comparision toGreseofulvin and Nystatin.Biological activity…

Studies on some compounds… 369TABLE - 5a:- ANTIMICROBIAL ACTIVITY OF 2,3-DICHLORO-N-[3-{3-ARYL-1[H] PYRAZOLINE -5-YL}PHENYL] BENZAMIDE.Biological activity…

Studies on some compounds… 370GRAPHICAL CHART-5a:- ANTIMICROBIAL ACTIVITY OF 2,3-DICHLORO-N-[3-{3-ARYL-1[H]PYRAZOLINE -5-YL}PHENYL] BENZAMIDEBiological activity…

Studies on some compounds… 371RESULTS AND DISCUSSION:ClClHNONHRNANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds oftype (V) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= phenyl, 2-thiophene, m-nitro phenyl and 3-methoxy 4-hydroxy phenyl substitutes against E.coli.and R= m-nitro phenyl, 4-chloro phenyl substitutes against P. aeruginosa incomparision to standard drug Ampicillin. However the compounds beaing N,Ndimethylphenyl substitutes is also giving significant activity against S. aureus .incomparision to standard dug Ampicillin.The significant activity was displayed by the compounds bearing R=pmethoxyphenyl, 3,4-dimethoxy phenyl and 3-phenoxy phenyl substitutes againstE.coli. and S. aureus respectively n comparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= phenyl, p-chloro phenyl, m-bromophenyl, and 3,4 dimethoxy phenyl substitutes indicate significant activity incomparision to Greseofulvin against C.albicans. While compound bearing R= m-phenoxy phenyl substitute indicates maximum activity in comparision to Nystatinand significant activity against Greseofulvin.The maximum activity was observed also in compounds bearing 3,4-dimethoxy phenyl, m-nitro phenyl substitutes and m-phenoxy phenyl substitutesagainst A.niger and A.clavatus in comparision to standard drug Nystatin andGreseofulvin.Biological activity…

Studies on some compounds… 372TABLE- 6a:-ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO- N – [3-{3-(ARYL) -1-PHENYL -1[H]PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.Biological activity…

Studies on some compounds… 373GRAPHICAL CHART- 6a:- ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO- N – [3-{3-(ARYL) -1-PHENYL -1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.Biological activity…

Studies on some compounds… 374RESULTS AND DISCUSSION:ClClORHNNNANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(VI) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= m-Methoxyphenyl, 3,4-dimethoxy phenyl, 2-thiophene substitutes against E.coli. and S. aureus,R= m-nitro phenyl substitutes against S. pyogenus in comparision to standard drugAmpicillin.However in the case of P. aeruginosa all the compounds are givingmaximum activity except R=phenyl, m-phenoxy phenyl and N,N-dimethylsubstitutes.The significant activity was displayed by the compounds bearing R= p-methoxy phenyl against E.coli and 3,4-dimethoxy phenyl and m-phneoxy phenylagainst S. aureus in comparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= m-phenoxy phenyl, p-chloro phenyl andindicate significant activity in comparision to Greseofulvin against C.albicans.While compounds bearing R= p-methoxy phenyl substitute is indicating significantactivity against A.niger in comparision to standard drugs Nystatin and Greseofulvin.Biological activity…

Studies on some compounds… 375TABLE-7a:-ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO- N–[3-{3-(ARYL)-1-ACETYL-1[H]-PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE].Biological activity…

Studies on some compounds… 376GRAPHICAL CHART-7a:-ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO- N –[3-{3-(ARYL)-1-ACETYL - 1[H] -PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE].Biological activity…

Studies on some compounds… 377RESULTS AND DISCUSSION:ClClHNONRNOCH 3ANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(VII) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= p-Methoxyphenyl, 3,4-dimethoxy phenyl, m-phenoxy phenyl, 4-hydroxy-3-methoxy phenylsubstituents against E.coli., R= m-bromo phenyl, 3-methoxy 4-hydroxy phenylsubstitutes against P. aeruginosa and p-methoxy phenyl, N,N-dimethyl phenyl, m-bromo phenyl substitutes against S. pyogenus in comparision to standard drugAmpicillin.However The compounds beaing 4-N,N-dimethyl phenyl and m-bromo phenylsubstitutes are giving significant activity against S. aureus in comparision tostandard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= 3,4-dimethoxy phenyl and m-bromophenyl indicate maximum activity in comparision to Nystatin and Greseofulvinagainst A. niger. And compounds bearing R= 3,4 –dimethoxy phenyl and 4-hydroxyl-3-methoy phenyl substitutes are also giving maximum activity incomparision to Greseofulvin and Nystatin against A. clavatus.While in case of C. albicans all the compounds except R = 3,4-dimethoxyphenyl, 2-thiphene and p-chloro phenyl are giving significant activity againstC.albicans in comparision to Greseofulvin.Biological activity…

Studies on some compounds… 378TABLE-8a:- ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO-N–[3-{3-(ARYL)-1-THIOCARBA MIDO -1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.Biological activity…

Studies on some compounds… 379GRAPHICAL CHART-8a:- ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO-N–[3-{3-(ARYL)-1-THIOCARBAMIDO - 1[H] PYRAZOLINE – 5 - YL} PHENYL] BENZAMIDE.Biological activity…

Studies on some compounds… 380RESULTS AND DISCUSSION:ClClHNONRNSNH 2ANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(VIII) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= 3,4-dimethoxy phenyl, 4-hydroxy 3-methoxy phenyl substitutes against E.coli., R = m-phenoxy against P. aeruginosa, R= 3,4- dimethoxy phenyl, m-phenoxy phenyl andm-nitro phenyl substitutes against S. pyogenus in comparision to standard drugAmpicillin.However the compounds beaing N,N-dimethyl phenyl, 4-hydroxy-3methoxyphenyl substitutes are giving significant activity against S. aureus.in comparision tostandard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= m-bromo phenyl indicate maximumactivity in comparision to Nystatin and Greseofulvin against A.clavatus. While incase of C. albicans all the compounds except R= phenyl, N,N-dimethyl phenylsubstitutes are giving significant activity against C.albicans in comparision toGreseofulvin.Biological activity…

Studies on some compounds… 381TABLE - 9a:- ANTIMICROBIAL ACTIVITY OF 2,3-DICHLORO-N– [3-{4-(ARYL)-2-MERCAPTO-1,4,-DIHYDRO PYRIMIDINE-6-YL}] BENZAMIDE.Biological activity…

Studies on some compounds… 382GRAPHICAL CHART - 9a:- ANTIMICROBIAL ACTIVITY OF 2, 3-DICHLORO- N – [3-{4-(ARYL)-2-MERCAPTO -1, 4,-DIHYDRO PYRIMIDINE -6-YL}] BENZAMIDE.Biological activity…

Studies on some compounds… 383RESULTS AND DISCUSSION:ClClRONHNNHSANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(IX) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= phenyl, 2-thiophene and p-chloro phenyl substitutes against E.coli, R= p-methoxy phenyl, 2-thiophene, m-bromo phnyl against P. aeruginosa and R = 3,4-dimethoxy phenylsubstitutes against S. pyogenus in comparision to standard drug Ampicillin.However the compounds beaing R = p-methoxy phenyl, phenyl, 2-thiopheneand m-bromo phenyl substitutes against S.aureus, are also giving significant activityin comparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-methoxy phenyl, 3,4-dimethoxy phenyl,phenyl, N,N-dimethyl phenyl, m-bromo phenyl and 4-hydroxy-3-methoxy phenylsubstitutes indicate significant activity in comparision to Greseofulvin againstC.albicans. While compound bearing R= N,N-dimethyl phenyl substitute is alsogiving maximum activity against A. niger in comparision to Greseofulvin andNystatin.Biological activity…

Studies on some compounds… 384TABLE-10a:-ANTIMICROBIAL ACTIVITY OF 2,3-DICHLORO- N-[3-(2-AMINO-4- ARYL-3-CYANOPYRIDINE-6-YL)] BENZAMIDE.Biological activity…

Studies on some compounds… 385GRAPHICAL CHART-10a:-ANTIMICROBIAL ACTIVITY OF 2,3-DICHLORO- N-[3-(2-AMINO-4-ARYL-3-CYANO PYRIDINE-6-YL)] BENZAMIDE.Biological activity…

Studies on some compounds… 386RESULTS AND DISCUSSION:ClClHNORNNH 2NANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(X) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= 3,4-dimethoxy phenyl, p-chloro phenyl substituent against E.coli., R= m-phenoxy phenyl,N,N-dimethyl phenyl, p-chloro phenyl and 4-hydroxy-3-methoxy phenyl substitutesagainst P. aeruginosa in comparision to standard drug Ampicillin.The significant activity was displayed by the compounds bearing R= p-methoxy phenyl substitutes against S. aureus and S. pyogenus, R = N,N- dimethylphenyl, 4- chloro phenyl and 4-hydroxy-3-methoxy phenyl substitutes against S.aureus in comparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However all the compounds except R = phenyl and p-chloro substitutes aregiving significant activity against C.albicans in comparision to Greseofulvin.Biological activity…

Studies on some compounds… 387TABLE-11a:- ANTIMICROBIAL ACTIVITY OF 4-ARYL-[5-(3,4–DIMETHYL)-PHENYL AMINOCARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.Biological activity…

Studies on some compounds… 388GRAPHICAL CHART:-11a:- ANTIMICROBIAL ACTIVITYOF 4-ARYL -[5 - (3, 4–DIMETHYL)-PHENYL AMINOCARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-ONES.Biological activity…

Studies on some compounds… 389RESULTS AND DISCUSSION:H 3 CCORH 3NHNHNHOANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(XI) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= phenyl, m-nitro phenyl substitutes against E.coli. R = m-phenoxy phenyl, m-nitro phenyl, N,Ndimethylphenyl and p-hydroxy phenyl against P. aeruginosa and p-methoxy phenylagainst S.pyogenus in comparision to standard drug Ampicillin.The significant activity was displayed by the compounds bearing R= p-methoxy phenyl substitutes against E.coli and P. aeruginosa ,R= p-hydroxy phenylsubstitutes against E.coli and in comparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-hydroxy phenyl indicate significantactivity in comparision to Greseofulvin and maximum activity in comparision toNystatin against C.albicans.While compounds bearing R= m-phenoxy phenyl, m-nitro phenyl, N,Ndimethylphenyl and p- chloro phenyl substitutes are also giving significant activityagainst C.albicans in comparision to Greseofulvin.Biological activity…

Studies on some compounds… 390TABLE-12a:- ANTIMICROBIAL ACTIVITYOF N-PHENYL-4-ARYL-[5-(3,4-DIMETHYL)-PHENYL AMINOCARBONYL]–6–PHENYL-1,4-DIHYDROPYRIMIDINE-2 (1H) -ONES.Biological activity…

Studies on some compounds… 391GRAPHICAL CHART-12a:- ANTIMICROBIAL ACTIVITY OF N-PHENYL-4-ARYL-[5-(3,4 -DIMETHYL)-PHENYLAMINOCARBONYL]–6–PHENYL-1,4-DIHYDROPYRIMIDINE-2 (1H) -ONES.Biological activity…

Studies on some compounds… 392RESULTS AND DISCUSSION:H 3 CCORH 3NHNNHOANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(XII) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= p-Methoxyphenyl, m-phenoxy phenyl, p- chloro phenyl substitutes against E.coli. R= 3,4-dimethoxyphenyl substitute against P. aeruginosa in comparision to standard drugAmpicillin. However The compounds beaing p-chloro phenyl substitute is also givingmaximum activity against S. pyogenus.The significant activity was displayed by the compounds bearing R= 3,4-dimethoxy phenyl substitute against E.coli. and p-methoxy phenyl, 3,4-dimethoxyphenyl and N,N-dimethyl phenyl substitutes against S.aureus in comparision tostandard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-methoxy phenyl, m-nitro phenyl andN,N-dimethyl phenyl and 2-thiophene indicate maximum activity in comparision toNystatin, and significant activity in comparision to Greseofulvin against C.albicans.While compounds bearing R= m-nitro phenyl is also giving maximum activityagainst A. niger in comparision to Greseofulvin and Nystatin.Biological activity…

Studies on some compounds… 393TABLE-13a:-ANTIMICROBIAL ACTIVITY OF 4-ARYL-[5-(3,4–DIIMETHYL)- PHENYLAMINOCARBONYL]–6–PHENYL-1,4-DIHYDROPYRIMIDINE-2(1H)-AMINO.Biological activity…

Studies on some compounds… 394GRAPHICAL CHART-13a:- ANTIMICROBIAL ACTIVITY OF 4-ARYL-[5-(3,4–DIIMETHYL)-PHENYLAMINOCARBONYL]–6–PHENYL-1,4-DIHYDROPYRIMIDINE-2(1H)-AMINO.Biological activity…

Studies on some compounds… 395RESULTS AND DISCUSSION:H 3 CCORH 3NHNHNHNHANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(XIII) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= m-phenoxyphenyl, p- hydroxy phenyl and p- chloro phenyl substitutes against E.coli., P.aeruginosa, S.aureus, and S.pyogenus in comparision to standard drug Ampicillin.However the compounds bearing p-methoxy phenyl and m-phenoxy phenylsubstitutes are giving significant activity against E.coli., P. aeruginosa, S.aureus,and S.pyogenus in comparision to standard drug Ampicillin..ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compound bearing R= p-chloro phenyl substitute indicatemaximum activity in comparision to Nystatin and Greseofulvin against A. niger.While in case of C. albicans all compounds except 2-thiophene are giving significantactivity in comparision to Greseofulvin and maximum activity in comparision toNystatin.Biological activity…

Studies on some compounds… 396TABLE-14a:- ANTIMICROBIAL ACTIVITYOF 4-ARYL-[5-(3,4–DIMETHYL)-PHENYL AMINO CARBONYL]– 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-THIONES.Biological activity…

Studies on some compounds… 397GRAPHICAL CHART-14a:- ANTIMICROBIAL ACTIVITY OF 4-ARYL-[5-(3,4–DIMETHYL)-PHENYL AMINOCARBONYL] – 6 – PHENYL - 1, 4 -DIHYDROPYRIMIDINE-2(1H)-THIONES.Biological activity…

Studies on some compounds… 398RESULTS AND DISCUSSION:H 3 CCORH 3NHNHNHSANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(XIV) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R= phenyl, p-hydroxy phenyl and p-chloro phenyl substituents against E.coli. and P. aeruginosa,However the compounds beaing 4-hydroxy- 3-methoxy phenyl and m-phenoxyphenyl substitute is also giving maximum activity against P. aeruginosa, S. aureusand S. pyogenus in comparision to standard drug Ampicillin.The significant activity was displayed by the compounds bearing R= phenyl,p-methoxy phenyl, and 3-methoxy 4-hydroxy phenyl substitutes againstS. aureus incomparision to standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-methoxy phenyl, m-phenoxy phenylsubstitutes indicate maximum activity in comparision to Nystatin and Greseofulvinagainst A. niger, where p-methoxy phenyl substitute also giving maximum activityagains A. clavatus. In the case of C.albicans all compounds except R= 4-methoxyphenyl, 3,4-dimethoxy phenyl and p-chloro phenyl substitutes are giving significantactivity in comparision to standard drug Greseofulvin.Biological activity…

Studies on some compounds… 399TABLE-15a:-ANTIMICROBIAL ACTIVITY OF 2-ARYLIDENE–4-(4′-METHOXYPHENYL)-5-(3,4-DIMETHYLPHENYLAMINO)CARBONYL-6-PHENYL - 4,7- DIHYDRO THIAZOLO [3,2-α] - PYRIMIDINE 3-ONES.Biological activity…

Studies on some compounds… 400GRAPHICAL CHART-15a:- ANTIMICROBIAL ACTIVITY OF 2-ARYLIDENE–4-(4′-METHOXYPHENYL)-5-(3,4-DIMETHYL PHENYLAMINO)CARBONYL-6-PHENYL - 4,7- DIHYDRO THIAZOLO [3,2-α] -PYRIMIDINE 3-ONES.Biological activity…

Studies on some compounds… 401RESULTS AND DISCUSSION:H 3 COH 3 CCOOH 3NHNNSRANTIBACTERIAL ACTIVITY:It has been observed from the experimental data that all compounds of type(XV) were found to be mild to moderately active against Gram positive and Gramnegative bacterial strains.The maximum activity was observed in compounds bearing R=p-methoxyphenyl, m-phenoxy phenyl, p-hydroxy phenyl, and p-chloro phenyl substitutes againstE.coli. and P. aeruginosa in comparision to standard drug Ampicillin.However the compounds beaing phenyl, 3,4-dimethoxy phenyl, p-hydroxyphenyl and p-chloro phenyl substitutes are giving significant activity against E .coli.and S. aureus.The significant activity was displayed by the compounds bearing R= p-methoxy phenyl and p-hydroxy phenyl substitutes against S. pyogenus in comparisionto standard drug Ampicillin.ANTIFUNGAL ACTIVITY:The antifungal data revealed that compounds were least toxic to the fungalstrain. However the compounds bearing R= p-methoxy phenyl, m-phenoxy phenyl, 2-thiophene and p-chloro phenyl indicate maximum activity in comparision toNystatin and significant activity in comparision to Greseofulvin against C.albicans.While compounds bearing R= m- phenoxy substitute was displayed maximumactivity against A.niger and m-nitro substitute against A. clavatus in comparision toGreseofulvin and Nystatin.Biological activity…

Studies on some compounds… 402[B]ANTITUBERCULAR ACTIVITYThe antitubercular evaluation of the selected compounds was carried out atMicrocare Laboratories and Tuberculosis Research Center- SURAT.INTRODUCTION:MYCOBACTERIUM:-Hansen [1868] discovered the first member [lepra bacilli], Robert Koch[1882] isolated mammalian tubercle bacilli and Johne [1895] describedMycoparatuberculosis [Johne’s bacillus]. Mycobacteria are slender bacilli andsometimes exhibit filamentous forms resembling fungal mycelium [from Greek,Myces meaning fungus] and hence they are so named. They are difficult to stain byordinary stains because of the presence of waxy materials in their cell walls. Althoughthey are gram positive, they stain poorly, if at all, by gram’s technique. They arebetter stained by hot carbol fuchsin, and once stained; they resist decolourisation bydilute minerals acids and are, therefore, referred to as Acid Fast Bacilli or AFB. Theseorganisms are non motile, non capsulated, non sporing and mostly very slow growing.The genus includes obligate parasites pathogenic to man, mammals; birds andreptiles, opportunistic pathogens and saprophytic varieties.MYCOBACTERIUM TUBERCULOSIS:-Morphology: -These are nonmotile, nonsporing and no capsulated bacilli, arranged singly orin groups. They are acid-fast due to the presence of mycolic acid in cell-wall andweakly Gram positive. With Ziehl-Neelsen stain, M.tuberculosis look slender, straightor slightly curved rod with beaded or barred appearance and M.bovis appearstraighter, stouter and shorter with uniform staining.Culture: -Tubercle bacilli are aerobes, grow slowly (generation time 14-15 hours),optimum temperature 37 0 C, pH 6.4-7.0. They grow only in specially enriched mediacontaining egg, asparagines, potatoes, serum and meat extracts. Colonies appear in 2-Biological activity…

Studies on some compounds… 4036 weeks. M.tuberculosis grows more luxuriantly in culture (eugenic) than M.boviswhich grows sparsely (dysgenic).The drug susceptibility test may be performed by either the direct or theindirect method. The direct drug susceptibility test is performed by using a subculturefrom a primary culture as the inoculums.EVALUTION TECHNIQUES:-Three well-known measures of sensitivity test are available:(1) The minimal inhibitor concentration or the MIC,(2) The resistance ratio or the RR, and(3) The proportion method.These tests are set up on solid media.(1) The minimal inhibitor concentration:Mic is defined as the minimal concentration of the drug required to inhibit thegrowth of the organisms, where growth is defined as 20 colonies or more .Thisdefinition of growth is chosen so that only a small proportion (e.g. 1%) of wild strainswould be classified as resistant by its use. This method is simple and be carried outwith a single drug containing slope although it is preferable to use more than oneslope.(2) Resistance ratio:This consists of expression the resistance as a ratio of the MIC of a test strainto that of control strain. This procedure calls for a rigid standardization since theinherent technical errors usually make it less efficient than the MIC method indistinguishing sensitive and resistant strains. A further disadvantage of the use of RRis that there may be more variation in sensitivity of the control strain than in wildstrain resulting in increase in the error. However, the RRs’ are more than one slope.(3) Proportion method:This method of testing sensitivity has a high degree of precision. Theinoculum suspension is standardized by weight of the bacilli and serial ten-folddilution of the suspension are made for seeding onto drug free and drug containingslopes. The proportion of resistant depending on the proportion. Two variants, asimplified variant and standard variant, are over a period of years.Biological activity…

Studies on some compounds… 404We have used the minimal inhibition concentration to evaluate the antituberculosisactivity. It is one of the non automated in vitro bacterial susceptibilitytests. This classic method yields a quantitative result for the amount of antimicrobialagents that is needed to inhibit growth of specific microorganisms. It is carried out inbottle.DETERMINATION OF MINIMAL INHIBITION CONCENTRATIONS BYL.J SLOPE METHOD:MATERIALS AND METHOD:-1. All the Synthesized Drugs Were Used For Anti-tubercle Test Procedures2. All Necessary Controls Like:ØØØØØØDrug ControlVehicle ControlAgar ControlOrganism ControlKnown Antibacterial Drugs ControlM.Tuberculosis H37 rv Cultures Were Tested Against AboveMentioned Known and Unknown Drugs.ØL.J Was Used As Nutrient Medium To Grow And Dilute The DrugSuspension For The Test.ØØInoculum Size for Test Strain Was Adjusted to 1mg/ml.Following common standard strain is used for screening of antitubercleactivities: The strains were procured from Institute of Microbial Technology,Chandigarh.· Mycobacterium tuberculosis H37Rv [Acid Fast Bacilli]· DMSO was used as diluents / vehicle to get desired concentration ofdrugs to test upon Standard bacterial strains.METHODS USED FOR PRIMARY AND SECONDARY SCREENING:Each synthesized drug was diluted obtaining 2000 micro gram /mlconcentration, as a stock solution.Biological activity…

Studies on some compounds… 405Primary screen: In primary screening 500 micro/ml, 250 micro/ml, and 125micro/ml concentrations of the synthesized drugs were taken. The activesynthesized drugs found in this primary screening were further tested in asecond set of dilution against all microorganisms.Secondary screen: The drugs found active in primary screening weresimilarly diluted to obtain 100 micro/ml, 50 micro/ml, 25 micro/ml, 12.5micro/ml, 6.250 micro/ml, 3.125 micro/ml and 1.5625 micro/mlconcentrations.Reading Result:-The highest dilution showing at least 90 % inhibition is taken as MIC.Theresult of this is much affected by the size of the inoculum. The test mixtureshould contain 10 8 organism/ml.The Standard Drugs:-The Standard strain M.tuberculosis, H 37 RV is tested with each new batchof medium. The recommended drug concentrations are 4 mg/l forstreptomycin, 0.2 mg/l for isoniazide, 40 mg/l for Rifampicin and 2 mg/ l forethambutol.METHOD : L.J.MEDIUM [CONVENTIONAL METHOD]BACTERIA : MYCOBACTERIA TUBERCULOSIS H37RVCONCENTRATION : 1000, 500, 250, 125, 100, 62.50, 50, 25, 12.5, 6.25µg/ml.STANDARD DRUGS : ISONIAZID.The antitubercular activity data have been compared with standard drugIsoniazid at different concentration and which showed 98 % Inhibition, the data of %inhibition are recorded in Table No.1b and onwards.Biological activity…

Studies on some compounds… 406TABLE:-1b:-ANTITUBERCULAR ACTIVITY OF 2,3-DICHLORO-N-(3-SUBSTITUTED STYRYL CARBONYL) BENZAMIDE.ClClOOHNRSr. CODE Where, MTb MIC % REMARKSNo. NO.R = Strain µg/ml Inhibition1 MM # 01 3,4-(OCH 3 ) 2 -C 6 H 4 H37R V 12.5 99% ISONIAZID =0.20 µg/ml2 MM # 02 4-OCH 3 -C 6 H 4 - H37R V 250 98% 98% inhibition3 MM # 03 4-Cl- C 6 H 4 H37R V 500 98%Biological activity…

Studies on some compounds… 407TABLE:-2b:- ANTITUBERCULAR ACTIVITY OF 2,3-DICHLORO- N- [3- {3-ARYL-1[H] PYRAZOLINE-5-YL} PHENYL] BENZAMIDE.ClClORHNNNHSr. CODE Where, MTb MIC % REMARKSNo. NO.R = Strain µg/ml Inhibition1 MM # 01 4-OCH 3 -C 6 H 4 - H37R V 100 99% ISONIAZID =0.20 µg/ml2 MM # 02 3,4-(OCH 3 ) 2 -C 6 H 4 H37R V 500 98% 98% inhibition3 MM # 03 4-Cl- C 6 H 4 H37R V 500 98%Biological activity…

Studies on some compounds… 408TABLE:-3b:-ANTITUBERCULAR ACTIVITY OF 2, 3-DICHLORO- N – [3-{3-(ARYL)-1-PHENYL - 1[H] PYRAZOLINE – 5 - YL} PHENYL]BENZAMIDE.ClClORHNNNSr. CODE Where, MTb MIC % REMARKSNo. NO. R = Strain µg/ml Inhibition1 MM # 01 4-OCH 3 -C 6 H 4 - H37R V 500 98% ISONIAZID =0.20 µg/ml2 MM # 02 4-Cl- C 6 H 4 H37R V 500 98% 98% inhibition3 MM # 03 3-Br- C 6 H 4 H37R V 250 98%Biological activity…

Studies on some compounds… 409TABLE:-4b:-ANTITUBERCULAR ACTIVITY OF SYNTHESIS ANDSTRUCTURE ELUCIDATION OF 2,3-DICHLORO-N-[3-(2-AMINO-4-ARYL-3-CYANO PYRIDINE-6-YL)] BENZAMIDE.ClClROCNHNN NH 2Sr. CODE Where, MTb MIC % REMARKSNo NO.R = Strain µg/ml Inhibition1 MM # 01 4-OCH 3 -C 6 H 4 - H37R V 250 98% ISONIAZID =0.20 µg/ml2 MM # 02 3,4-(OCH 3 ) 2 -C 6 H 4 H37R V 500 98% 98% inhibition3 MM # 03 3-C 6 H 5 -O-C 6 H 4 H37R V 500 98%Biological activity…

LIST OF NEW COMPOUND

ClClORClClORHNNNHHNNNRR4-OCH 3 -C 6 H 4 - 4-OCH 3 -C 6 H 4 -C 6 H 5 - C 6 H 5 -3,4-(OCH 3 ) 2 -C 6 H 4- 3,4-(OCH 3 ) 2 -C 6 H 4-C 4 H 7 SC 4 H 7 S3-C 6 H 5 -O-C 6 H 4 - 3-C 6 H 5 -O-C 6 H 4-4-N(CH 3 ) 2 -C 6 H 4- 4-N(CH 3 ) 2 -C 6 H 4-4-Cl- C 6 H 4- 4-Cl- C 6 H 43-Br- C 6 H 4- 3-Br- C 6 H 4-3-NO 2 -C 6 H 4 - 3-NO 2 -C 6 H 4 -4-OH,3-OCH 3- C 6 H 3- 4-OH,3-OCH 3- C 6 H 3-ClClClHNONRNOCH 3\\\ClHNONRNSNH 2RR4-OCH 3 -C 6 H 4 - 4-OCH 3 -C 6 H 4 -C 6 H 5 - C 6 H 5 -3,4-(OCH 3 ) 2 -C 6 H 4- 3,4-(OCH 3 ) 2 -C 6 H 4-C 4 H 7 SC 4 H 7 S3-C 6 H 5 -O-C 6 H 4 - 3-C 6 H 5 -O-C 6 H 4-4-N(CH 3 ) 2 -C 6 H 4- 4-N(CH 3 ) 2 -C 6 H 4-4-Cl- C 6 H 4- 4-Cl- C 6 H 43-Br- C 6 H 4- 3-Br- C 6 H 4-3-NO 2 -C 6 H 4 - 3-NO 2 -C 6 H 4 -4-OH,3-OCH 3- C 6 H 3- 4-OH,3-OCH 3- C 6 H 3-

OOH 3 CNH NCH 3RCH 3H 3 CN NOORRR4-OCH 3 -C 6 H 4 - 4-OCH 3 -C 6 H 4 -C 6 H 5 - C 6 H 5 -3-NO 2 -C 6 H 4 - 3-NO 2 -C 6 H 4 -4-OH-C 6 H 5-4-OH-C 6 H 5-4-OH,3-OCH 3 , 5-NO 2 C 6 H 2-4-OH,3-OCH 3 , 5-NO 2 C 6 H 2-3-C 6 H 5 -O-C 6 H 43-C 6 H 5 -O-C 6 H 44-N(CH 3 ) 2 -C 6 H 44-N(CH 3 ) 2 -C 6 H 43,4-(OCH 3 ) 2 -C 6 H 43,4-(OCH 3 ) 2 -C 6 H 44-OH,3-OCH 3 -C6H 3 4-OH,3-OCH 3 -C6H 3C 4 H 7 SC 4 H 7 SCH 3H 3 CN NOOSNHRClClONHORRR4-OCH 3 -C 6 H 4 -4-NO 2 -C 6 H 4 -4-Cl-C 6 H 4 -3,4-(CH 3 ) 2- C 6 H 4 -4-CH 3 -C 6 H 4 -2,4(CH 3 ) 2 -C 6 H 43-NO 2 -C 6 H 4C 6 H 52-CH 3 -C 6 H 43-Cl-C 6 H 44-OCH 3 -C 6 H 4 -C 6 H 5 -3,4-(OCH 3 ) 2 -C 6 H 4C 4 H 7 S3-C 6 H 5 -O-C 6 H 44-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 43-Br- C 6 H 43-NO 2 -C 6 H 4 -4-OH,3-OCH 3- C 6 H 3

RRClClClClHNONHNSHNONNH 2NR4-OCH 3 -C 6 H 4 -C 6 H 5 -3,4-(OCH 3 ) 2 -C 6 H 4C 4 H 7 S3-C 6 H 5 -O-C 6 H 44-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 43-Br- C 6 H 43-NO 2 -C 6 H 4 -4-OH,3-OCH 3- C 6 H 3R4-OCH 3 -C 6 H 4 -C 6 H 5 -3,4-(OCH 3 ) 2 -C 6 H 4C 4 H 7 S3-C 6 H 5 -O-C 6 H 44-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 43-Br- C 6 H 43-NO 2 -C 6 H 4 -4-OH,3-OCH 3- C 6 H 3RROOH 3 CCH 3NHNHH 3 CCH 3NHNNHONHOR4-OCH 3 -C 6 H 4 -C 6 H 5 -3-C 6 H 5 -O-C 6 H 43,4-(OCH 3 ) 2 -C 6 H 44-OH,3-OCH 3- C 6 H 33-NO 2 -C 6 H 4 -C 4 H 7 S4-OH-C 6 H 5-4-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 4R4-OCH 3 -C 6 H 4 -C 6 H 5 -3-C 6 H 5 -O-C 6 H 43,4-(OCH 3 ) 2 -C 6 H 44-OH,3-OCH 3- C 6 H 33-NO 2 -C 6 H 4 -C 4 H 7 S4-OH-C 6 H 5-4-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 4

RROOH 3 CCH 3NHNHH 3 CCH 3NHNHNHNHNHSR4-OCH 3 -C 6 H 4 -C 6 H 5 -3-C 6 H 5 -O-C 6 H 43,4-(OCH 3 ) 2 -C 6 H 44-OH,3-OCH 3- C 6 H 33-NO 2 -C 6 H 4 -C 4 H 7 S4-OH-C 6 H 5-4-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 4R4-OCH 3 -C 6 H 4 -C 6 H 5 -3-C 6 H 5 -O-C 6 H 43,4-(OCH 3 ) 2 -C 6 H 44-OH,3-OCH 3- C 6 H 33-NO 2 -C 6 H 4 -C 4 H 7 S4-OH-C 6 H 5-4-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 4H 3 COH 3 CCOOH 3NHNNSRR4-OCH 3 -C 6 H 4 -C 6 H 5 -3-C 6 H 5 -O-C 6 H 43,4-(OCH 3 ) 2 -C 6 H 44-OH,3-OCH 3- C 6 H 33-NO 2 -C 6 H 4 -C 4 H 7 S4-OH-C 6 H 5-4-N(CH 3 ) 2 -C 6 H 44-Cl- C 6 H 4