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Saurashtra UniversityRe – Accredited Grade ‘B’ by NAAC(CGPA 2.93)Savaliya, Mahendra D., 2010, “Synthesis and Therapeutic activity of some newpiperazine Derivatives”, thesis PhD, Saurashtra Universityhttp://etheses.saurashtrauniversity.edu/id/eprint/458Copyright and moral rights for this thesis are retained by the authorA copy can be downloaded for personal non-commercial research or study,without prior permission or charge.This thesis cannot be reproduced or quoted extensively from without firstobtaining permission in writing from the Author.The content must not be changed in any way or sold commercially in anyformat or medium without the formal permission of the AuthorWhen referring to this work, full bibliographic details including the author, title,awarding institution and date of the thesis must be given.Saurashtra University Theses Servicehttp://etheses.saurashtrauniversity.edurepository@sauuni.ernet.in© The Author

“SYNTHESIS AND THERAPEUTICACTIVITY OF SOME NEWPIPERAZINE DERIVATIVES”A THESISSUBMITTED TO THESAURASHTRA UNIVERSITYFOR THE DEGREE OFDOCTOR OF PHILOSOPHYINTHE FACULTY OF SCIENCE (CHEMISTRY)BYMAHENDRA D. SAVALIYAUNDER THE GUIDANCEOFDr. D. M. PUROHITSHREE M. & N. VIRANI SCIENCE COLLEGE,DEPARTMENT OF CHEMISTRY,KALAWAD ROAD,RAJKOT – 360 005.INDIA2010

Date: 26/ 04 /2010Dr. D. M. PurohitResidence:M. Sc. Ph. D., Dr. D. M. PurohitLecturer,B-149,"shandilya"Shree M. & N. Virani Science CollegeShastrinagar,Department of chemistry,Nana Mova Road,Kalawad Road Rajkot – 360 005Rajkot – 360 005 Gujarat (India).Statement under O. Ph. D. 7 of Saurashtra UniversityThe work included in the thesis is my own work under the supervisionof Dr. D. M. Purohit and leads to some contribution in Chemistry subsidised by anumber of references.Date: 26 / 04 / 2010Place : Rajkot.(Mahendra D. Savaliya)This is to certify that the present work submitted for the Ph. D. Degree ofSaurashtra University by Mahendra D. Savaliya is his own work and leads toadvancement in the knowledge of chemistry. The thesis has been prepared under mysupervision.Date: 26 / 04 / 2010Place: Rajkot.(Dr. D. M. Purohit)Lecturer,Shree M. & N. Virani Science CollegeDepartment of ChemistryKalawad Road.Rajkot – 360 005.Gujarat (India).

DedicatedToMy Family

ACKNOWLEDGEMENTS“ JAY GIRNARI ”Hats off to the Omnipresent, Omniscient and Almighty God, the gloriousfountain and continuous source of inspirations! I offer salutations to him and myhead bows with rapturous dedication from within my heart, to the Omnipotent Lord“ JAY GURUDATT ” and my ideal “ SWAMI VIVEKANANDA ”An endeavour such as a Ph.D. is impossible to accomplish without thegenerous help and support of my family, friends and colleagues. I would like to takethis opportunity to thank those whom I was fortunate to know, work, and formfriendship with over the past three years.First, I wish like to express my deep appreciation and gratitude to my cotravelerand guide Dr. D. M. Purohit Lecturer, Chemistry Department, shree M.&N. Virani science college, Rajkot. His dedication to science, unwavering demand forexcellence from him self has set up a high standard for his students to look up to andto follow. I appreciated the freedom he allowed, which permitted me to developscientific thoughts and experimental skills independently, lofty research methodologyand the motivation as well as them highly punctual affectionate encouragement andoccasional constructive criticism when needed, towards the goal of my academicjourney.I also owe to, from the deepest corner of heart, deepest sense of gratitude andindebtedness to Dr. V. N. Patolia, Head, Chemistry Department, Kamani sciencecollege, Amreli, as I have been constantly benefited with them.Who is in this world can not entirely and adequately thank the parents whohave given us everything that we possess in this life ? The life itself is their gift tous, so I am at loss of words in which I express myself to my most esteemed fatherShri Dhirubhai and my loving mother Smt. Prabhaben, who had always wished thatI scale many more heights of success in the field of research. I pay my humblerespects to my grand father Bavabapa and grand mother Hemba. Through the stress

and strain of this study, I can never forget to express my special gratitude to mybeloved younger brother Sanjay and younger sister Manisha, whose unstopping flowof love and encouraged me to reach my destination. I wish to thank my uncle, myaunty and all other family members.I am deeply indebted to my best friend Dr. Jitendra G. Dobaria and Mr.Jagdish Makwana for his help, suggestions, encouragement and kindness that mademy research work success.I feel great pleasur to acknowledge my deepest sense of indebtedness to Mr.Mahendra G. Dobaria and Mr. Kalpesh Vadadoriya for her invaluable inspirationand moral support throught the course of my research work.I wish to thank Dr. Jayesh V. Guna, Dr. Vipul V. Bhuva and PareshKathiriya for his most willing co-operation and comprehensive exchange of ideasduring the course of my research work.I offer my heart full gratitude to Dr. Hitin Hirpara, Dr. Viral Parekh,Dr. Snehal Dhol, Dr. Harshad Sangani, Dr. Ranjanben, Dr. Ashok Patel, Dr. VijayLunagariya, Dr. Dinesh Paghdar, Dr. Sajid, Dr. Dinesh Bhoot, Dr. Kanji Bhimani,Dr. Ramesh Kanparia and Dr. Chirag Bhuva for their support and much fruitfuldiscussion at various stages. I am most thankful to all my juniors for their valuableco-operation and help during the course of my research work.I feel lucky and very proud to have intimate friends like Pravinbhai(PSP),Majidbhai, Bhaveshbhai, Rajubhai, Vivek, Prashant, Jasmin, Rajni, Suresh,Hitendra, Arvind, Chinal, Safi, Ashwin, Ujjwal, Reena, Priya, Vinita, Jignesh,Daxesh, Lalitbhai, Lalji, Amit, Rohit, Yogesh and Mukesh, who have been alwaysparticipated with my problems, encouraged and rebuilt my confidence at appropriatestages.As with the completion of this task, I find myself in difficult position onattempting to express my deep indebtedness to Dr. Hitesh T. Kubavat and Mr.Manish G. Gondaliya for their kind support during the course of my research work.

I wish to thank of all teaching staff members and non teaching staffmembers of Shree M. & N. Virani Science College, Rajkot for their valuablecooperation and help during the course of my research work.I gratefully acknowledge the most willing help and co-operation shown byDepartment of chemistry, Saurastra university, Rajkot. CSMCRI Bhavnagar, CILChandigadh for spectral studies .Finally, I am thankful to Principal and Management of Shree M. & N.Virani Science College, Rajkot for their kind support and provided me the excellentchemical research laboratory facility and glass wares on time his co-operation inmagnifying the presentation of my work in the form of thesis.Mahendra D. Savaliya

CONTENTSSYNOPSIS . . . . . . 1SYNTHESIS AND THERAPEUTIC ACTIVITY OF SOME NEWPIPERAZINE DERIVATIVESGeneral Introduction . . . . . . 12Subject Introduction . . . . . . 16PART - I: STUDIES ON ARYLAMIDEIntroduction . . . . . . 29Section - I : Synthesis and biological Screening of 1-aroyl-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 33Experimental . . . . . . 39Graphical data of In Vitro Evaluation of Antimicrobial screening . . 44Section - II : Synthesis and biological Screening of 1-N-aroylamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 46Experimental . . . . . . 52Graphical data of In Vitro Evaluation of Antimicrobial screening . . 55PART - II : STUDIES ON SULPHONEMIDESIntroduction . . . . . . 57Section - I : Synthesis and biological Screening of 1-arylsulpho-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 62

Experimental . . . . . . 68Graphical data of In Vitro Evaluation of Antimicrobial screening . . 70Section - II : Synthesis and biological Screening of 1-N-arylsulphonamido-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 72Experimental . . . . . . 78Graphical data of In Vitro Evaluation of Antimicrobial screening . . 80PART - III : STUDIES ON MANNICH BASESIntroduction . . . . . . 82Section - I : Synthesis and biological Screening of 1-arylaminomethyl-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 88Experimental . . . . . . 94Graphical data of In Vitro Evaluation of Antimicrobial screening . . 96Section - II : Synthesis and biological Screening of 1-N-(arylaminomethylamino)-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 98Experimental . . . . . . 104Graphical data of In Vitro Evaluation of Antimicrobial screening . . 106PART - IV : STUDIES ON SCHIFF’S BASESIntroduction . . . . . . 108Section - I : Synthesis and biological Screening of 1-N-arylideneamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 114Experimental . . . . . . 120Graphical data of In Vitro Evaluation of Antimicrobial screening . . 122

Section - II : Synthesis and biological Screening of 1-N-arylmethylamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Introduction and Spectral studies ... . . . . 124Experimental . . . . . . 130Graphical data of In Vitro Evaluation of Antimicrobial screening . . 132PART - V : STUDIES ON 4-THIAZOLIDINONESIntroduction . . . . . . 134Section - I : Synthesis and biological Screening of 2-aryl-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-H-4-thiazolidinones.Introduction and Spectral studies ... . . . . 142Experimental . . . . . . 148Graphical data of In Vitro Evaluation of Antimicrobial screening . . 150Section - II : Synthesis and biological Screening of 2-aryl-3-N-{4'-[(4'',4"'-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-methyl-4-thiazolidinones.Introduction and Spectral studies ... . . . . 152Experimental . . . . . . 158Graphical data of In Vitro Evaluation of Antimicrobial screening . . 160Section - III : Synthesis and biological Screening of 2-aryl-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-carboxymethyl-4-thiazolidinones.Introduction and Spectral studies ... . . . . 162Experimental . . . . . . . . 168Graphical data of In Vitro Evaluation of Antimicrobial screening . . 170PART - VI : STUDIES ON 2-AZETIDINONESIntroduction . . . . . . . . 172

Section - I : Synthesis and biological screening of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-aryl-3-chloro-2-azetidinones.Introduction and Spectral studies ... . . . . 178Experimental . . . . . . . . 184Graphical data of In Vitro Evaluation of Antimicrobial screening . . 186PART- VII : STUDIES ON 5-OXO-IMIDAZOLINESIntroduction . . . . . . . . 188Section - I : Synthesis and biological Screening of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-arylidene-2-phenyl-5-oxoimidazolines.Introduction and Spectral studies ... . . . . 196Experimental . . . . . . . . 202Graphical data of In Vitro Evaluation of Antimicrobial screening . . 204Section - II : Synthesis and biological Screening of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-arylidene-2-(4""-methoxyphenyl)-5-oxo-imidazolines.Introduction and Spectral studies ... . . . . 206Experimental . . . . . . . . 212Graphical data of In Vitro Evaluation of Antimicrobial screening . . 214REFERENCES . . . . . . . . 216LIST OF PAPER PUBLICATIONS . . . . . . 247

“SYNTHESIS AND THERAPEUTIC ACTIVITY OFSOME NEW PIPERAZINE DERIVATIVES”SynopsisThe research work incorporated in the thesis entitled “SYNTHESIS ANDTHERAPEUTIC ACTIVITY OF SOME NEW PIPERAZINE DERIVATIVES”has been described as under.The aim of research is to develop new bioactive entities, especially withantimicrobial activities bearing a different piperazine derivatives nucleus. Numerouspiperazine derivatives like aryl amide, sulphonamides, Mannich bases, Schiff's bases,thiazolidinones, azetidinones, imidazolinones have been prepared. Above piperazinederivatives containing a wide spectrum of biological activities viz. anti-inflammatory,antibacterial, antimalarial, anticonvulsant, antipyretic, antitumor, anthelmintics,analgesic, antidepressant, antifungal, antitubercular, anticancer, antidiabetic etc.Taking in view of the applicability and chemical diversity in the molecular framework in order to interest synthesis, spectral studies and therapeutic activity of somenew piperazine derivatives.under.Some new synthesized piperazine derivatives which have been described asPART – I : STUDIES ON ARYLAMIDE.Arylamide derivatives showed different biological activity such asantihistamine, anti-inflammatory, anticonvulsant, antitubercular, antipyretic,analgesic, antiseptic, etc. With a view of getting better therapeutic agent and toevaluate its pharmacological profile. Some new aryl amide derivatives have beensynthesized. Which have been described as under.1

SynopsisSECTION-I : Synthesis and biological screening of 1-aroyl-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.FNNORType-IFR= ArylAryl amide of Type-(I) have been synthesized by the condensation of 1-(H)-4 -[(4',4"-difluoro diphenyl)-methyl]-piperazine with aroyl chloride.SECTION-II : Synthesis and biological screening of 1-N-aroylamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.FNNNHROFType-IIR= ArylArylamide of Type-(II) have been synthesized by the condensation of 1-amino -4-[(4',4"- difluorodiphenyl)-methyl]-piperazine with aroyl chloride.2

SynopsisPART – II : STUDIES ON SULPHONAMIDES.Sulphonamide derivatives have been found to be associated with variouspharmacological activities such as anti-inflammatory, antibacterial, tuberculosis,antimalarial, antiviral, anticonvulsant etc. These finding encouraged us to synthesizedsome new sulphonamide derivatives are as under.SECTION-I : Synthesis and biological screening of 1 - arylsulpho - 4 - [(4', 4"-difluorodiphenyl)-methyl]-piperazines.FONNSROFType-IIIR= ArylSulphonamides of Type-(III) have been synthesized by the condensationof 1 - (H) - 4 - [(4', 4"- difluorodiphenyl) - methyl]- piperazine with arylsulphonylchloride.SECTION-II : Synthesis and biological screening of 1 -N - arylsulphonamido -4-[(4',4"-diflurodiphenyl)-methyl]-piperazines.FNNNHSOORFType-IVR= Aryl3

SynopsisSulphonamides of Type-(IV) have been synthesized by the condensationof 1-amino- 4 -[(4',4"-difluorodiphenyl)-methyl]-piperazine with arylsulphonylchloride.PART – III : STUDIES ON MANNICH BASES.Mannich bases containing bridge N-atom exhibit diversepharmacological activities like anti-inflammatory, anthelmintics, antibacterial,antimalarial, antineoplastic, analgesic, anticonvulsant etc. Mannich bases are alsofound as intermediate in organic synthesis and good chelating agent hence it ispertinent to synthesized new Mannich base. which have been described as under.SECTION-I : Synthesis and biological screening of 1-arylaminomethyl-4- [(4',4"-difluorodiphenyl)-methyl] -piperazines.FNNNH RFType-VR= ArylMannich bases of Type-(V) have been synthesized by the condensation of1-(H)-4-[(4',4"-difluoro diphenyl)-methyl]-piperazine with aryl amine, formaldehydein presence of hydrochloric acid.4

SynopsisSECTION-I : Synthesis and biological screening of 1 - N - arylideneamino - 4 -[(4',4" -difluorodiphenyl)-methyl] -piperazines.FN N NRFType-VIIR= ArylSchiff’s base of Type-(VII) have been synthesized by the condensation of1- amino - 4 - [(4', 4"- difluorodiphenyl)- methyl]- piperazine with different aromaticaldehydes.SECTION-II : Synthesis and biological screening of 1 - N - arylmethylamino - 4 -[(4',4"-difluorodiphenyl)-methyl] -piperazines.FN N NHRFType-VIIIR= Aryl6

SynopsisThe compounds of Type-(VIII) have been synthesized by the reduction of 1-N-arylideneamino-4-[(4', 4"- difluorodiphenyl)- methyl]- piperazines of Type-(VII)with NaBH 4.PART-V : STUDIES ON 4-THIAZOLIDINONES.4-Thiazolidinones have been found to be associated with variousbiological activities such as antitubercular, anticonvulsant, antifungal, hypnotic,sedative,analgesic, antibacterial etc. In view of getting better therapeutic agent,we have synthesized some new 4-thiazolidinones derivatives which have beendescribed as under.FRNNNSOFType-IXR= Aryl4-Thiazolidinone derivatives of Type-(IX) have been synthesized by theheterocyclization of Schiff’s bases of Type-(VII) with thioglycolic acid.SECTION-I : Synthesis and biological screening of 2-aryl-3-N-{4'-[(4",4"'-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-H-4-thiazolidinones.SECTION-II: Synthesis and biological screening of 2-aryl -3 - N- { 4'-[( 4",4"'-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-methyl-4-thiazolidinones.7

SynopsisFRNNNSCH 38OFType-XR= Aryl4-Thiazolidinone derivatives of Type-(X) have been synthesized by theheterocyclization of Schiff’s bases of Type-(VII) with thiolactic acid.SECTION-III: Synthesis and biological screening of 2-aryl-3-N-{ 4'-[( 4",4"'-difluorodiphenyl )- methyl]- piperazine-1'-yl }-5- carboxymethyl-4-thiazolidinones.FRNNNSCOOHOFType-XIR= Aryl

Synopsis4-Thiazolidinone derivatives of Type-(XI) have been synthesized by theheterocyclization of Schiff’s bases of Type-(VII) with thiomalic acid.PART – VI : STUDIES ON 2-AZETIDINONES.2-Azetidinones derivatives represent one of the most active classes ofcompounds possessing a wide spectrum of biological activities such as antibiotic,antidepressant, sedative, hypnotic, anticonvulsant, antiviral etc, with a view to getbetter therapeutic agents, we have synthesized different types of 2-azetidinonederivatives which have been described as under.SECTION-I: Synthesis and biological screening of 1 - N - { 4' - [(4",4"'- difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-aryl-3-chloro-2-azetidinones.FRNNNClOFType-XIIR= Aryl2-Azetidinones of Type-(XII) have been synthesized by the chemoselective cyclization of Schiff’s bases of Type-(VII) with chloroacetyl chloride in thepresence of triethyl amine as a basic catalyst.PART-VII : STUDIES ON 5-OXO-IMIDAZOLINES.5-Oxo- imidazoline derivatives have been reported to be active asanticonvulsant, potent CNS depressant, anti-inflammatory, anticancer, sedatives,hypnotics and as mono amino oxidase (MAO) inhibitors etc. In view of obtaining9

Synopsisbetter therapeutic agents, we have synthesized some new 5-oxo-imidazolinederivatives which have been described as under.SECTION-I: Synthesis and biological screening of 1 - N - {4' -[(4", 4"'- difluorodiphenyl)- methyl]- piperazine-1'-yl} -4- arylidene-2- phenyl-5-oxo -imidazolines.FONNNNRFType-XIIIR= Aryl5-Oxo-imidazolines of Type-(XIII) have been synthesized by thecondensation of 1 - amino - 4 - [(4', 4"- difluorodiphenyl) - methyl]- piperazine withdifferent oxazolones.SECTION-II: Synthesis and biological screening of 1 - N - {4'- [(4", 4"'- difluorodiphenyl)- methyl]- piperazine-1'-yl}-4- arylidene-2-(4""- methoxyphenyl)-5-oxo-imidazolines.10

SynopsisFONNNNRFH 3 COType-XIVR= Aryl5-Oxo-imidazolines of Type-(XIV) have been synthesized by thecondensation of 1 - amino - 4 - [(4', 4"- difluorodiphenyl)- methyl]- piperazine withdifferent oxazolones.CHARACTERIZATIONS:The constitution of the synthesized products for structure elucidationhave been characterized using elemental analysis, IR, 1 H NMR spectroscopy andfurther supported by mass spectrometry. Purity of the compounds have been checkedby thin layer chromatography.STUDIES ON BIOLOGICAL ACTIVITIES :All the compounds have been also evaluated for their antibacterialactivity towards Gram positive and Gram negative bacterial strains and antifungalactivity towards Aspergillus niger at a concentration of 50 µg/ml. The biologicalactivities of the synthesized compounds have been compared with known standarddrugs.11

General IntroductionINTRODUCTIONResearch programs for the discovery of new drugs and for improving theevolution criteria are under way in many laboratories. In addition knowledge ofspecific constituents of the mycobacterium cell and their biochemical roles hasadvanced considerably in the recent years and may permit a more rationalapproach to the design of new drug action on specific targets. Also, recentimprovements in the knowledge of the mechanism of action of available drugs andthe biochemical mechanism of resistance to them may be used as a basis for designnew and better drugs to care the mycobacterial diseases.The current environment for discovery and development of newpharmaceuticals agents could hardly be ware challenging. Public policies andattitudes are requiring reduction in health care expenditures and increase efficiencies,resulting in major health care reform in the United States. At the sometime, majordiseases remain untreated and paradoxically, scientific progress continues with everincreasing acceleration.The last few decades have witnessed massive advances in biochemistry,physiology, pharmacology and genetics. This has to a better understanding ofworking the body at the molecular level. This in turn has resulted a much betterunderstanding of the structure and function of important drug targets e.g. enzymesand receptors and that how drugs can be designed for these targets.Advances in genetics engineering have been used to produce humanproteins and enzymes in fast growing microbial cells, allowing these molecules tobe obtained in far greater yields than if they were extracted from human tissue.This makes it easier to study these micro molecules and to design drugs that willinteract with them. Mapping of human DNA through human genome project hasimmense implications for medicinal chemistry.Advances in chemistry have made possible the synthesis of complexesmolecules. Enantiometry is an important process in medicinal chemistry since life isinherently chiral and the drug targets within the body are chiral. As such, they candistinguish between the enantiomers of a chiral drug, so the use of recemic drug is12

General Introductioninherently wasteful, since only one enantiomer is ideally designed to interactwith its target. Moreover, the existences of the “wrong” enantiomer could createproblems if it interacted with a different receptor, resulting inside effects.The focus of drug design has switched from structure oriented to targetoriented research, e.g. development of the antiulcer agent cimetidine. Histaminewas the lead compound for the project and various strategies were used to find ananalog that would prevent it fitting its receptor. Once an antagonist wasdeveloped, a theory was proposed on how it might interact with the histaminereceptor at a molecular level. Further analogs were then synthesized to test theoryand the theory was continusally modified as required.In the nineteenth century, chemistry developed as a science, both in terms ofexperimental procedures and scientific theory. Scientist isolated and purified singlecompounds from natural extracts. Method of organic synthesis were developedthat helped chemists altering structures in a predictable way.The chemists started separating out the various components of ancientpositions to discover whether a single compound was responsible for the medicinaleffect known as the active principle.Drugs are chemicals of low molecular weight (~100-500) which interact withmacromolecular targets to produce a biological response. The biological responsemay be therapeutically useful in the case of medicines or harmful in the case ofpoisons. Most drugs used in medicine are potential poisons if taken in higherdoses than recommended.Drugs are classified by their chemical structures. Drugs classified in this wayshare a common structural feature and often share similar pharmacologicalactivity. For example, all penicillin’s contain a β-lactum ring and kill bacteria by thesame mechanism, as a result, this classification can sometimes be useful inmedicinal chemistry. However, it is not foolproof. Sulfonamides have a similarstructure and are mostly antibacterial. However some sulfonamides are useful inthe treatment of diabetes. Similarly all steroids have a tetracyclic structure, but thepharmacological effect of different steroids can be quite different e.g. Testosteroneis a sex hormone and Spironolactone is a diuretic.13

General IntroductionFinally classifying drugs according to their molecular target is the most usefulclassification as far as medicinal chemist is concerned, since it allows a rationalcomparison of the structure involved.Such compounds either in extract form or in pure form become a part ofpharmacopoeia. For intanse, though the chinese drug, Mauhany was in use for over5000 years for the treatment of various types of fever and respiratory ailments,itsactive principle ephidrine was isolated in 1887. In 1925 chemical investigationsfollowed by pharmacological evaluation led this compound into the modern medicine.Similarly during this period, urea stibamine was introduced as the first drug in 1920for the treatment of Kala azar, in 1930 De Raywolfia preparation were first employedfor sedative and hypotensive properties.A drug is a substances having abnormal effect on certain body functionsestrichnine stimulates the action of heart and aspirin still it action since both of themeffects abnormally the two substances are known as drugs chemical sciencescontributed extensively new discoveries leading to useful drug after 1930.The modern concept of drug discovery supported in 1933 by GerhandDomayk with his finding of "Prontosil Red" a compound responsible for theantibacterial activity. The advert of sulphonamides draw attention to the differentacitvity of various chemicals for bacterial and human cells, this important factorprompted the Florey and chain in 1939 to investigate penicillins which wasdiscovered ten years earlier by Aexander Fleming.A large number of important drugs have been introduced during the period of1940 to 1960. This perod is knowns as 'Golden Period' of new drug discovery.Thusstarting from 1933-the first antibacterial drug prontosil leading various sulpha drugs;1940-penicillin; 1945-chloroquine (antimalarial); 1950-methyldopa (antidiabetic);1957-chlorothiaido (diuretic); 1958-adrenergic (beta blockers coronary vasodilatory);1960-semi synthetic penicillin (antibiotics); 1965-trimethoprim (antimicrobial); 1967-disodium chromoglycate (antiallergic); 1972-cimetidine (H 2 -antagonist); 1975-verampril (calcium antagonist); 1981-captopril (antihypertensive) etc. There are somespecific examples representing new therapeutics.The spectacular chemotherapeutical properties of penicillin and its dramatictime was development for the treatment of wound made penicillin, a most commonlyused inexpensive drug.14

General IntroductionThe word ‘drug’ is derived from the French word ‘drogue’ which means a dryherb. According to “WHO” a drug may be defined as “any substance or productwhich is used or intended to be used for modifying or exploring physiologicalsystem or pathological status for the benefit of recipient”.The ultimate product of a successful drug design effort. Our goal for this is tobegin to deconvolute this information in order to apply it to design of new drugs.Taking in view of the applicability of heterocyclic compounds, we have undertakenthe preparation of piperazine derivatives nucleus. The placement of a wide variety ofsubstituents of these nuclei has been designed in order to evaluate the synthesizedproducts for their pharmacological profile against several strains of bacteria and fungi.AIMS AND OBJECTIVESIn the pharmaceutical field, there is a need for new and novel chemicalinhibitors of biological functions. Our efforts are focused on the introduction ofchemical diversity in the molecular frame work in order to synthesizingpharmacologically interesting piperazine derivatives of widely different composition.During the course of research work looking to the applications of piperazinederivatives, several entities have been designed, generated and characterized usingspectral studies. The aims and objectives of the work carried out are as under.1. To synthesize pharmacologically active entities like arylamide,sulphonamides, Mannichbases, Schiff’s bases, thiazolidinones, 2-azetidinones,5-Oxo-imidazolines etc.2. To characterise these products for structural elucidation using spectroscopictechniques like IR, 1 H NMR and Mass spectral studies.3. To check the purity of all compounds using thin layer chromatography.4. To evaluate these new products for better drug potential against differentstrains of bacteria and fungi.15

Introduction of piperazine derivativesINTRODUCTION OF PIPERAZINE DERIVATIVESINTRODUCTIONPiperazine was used early in the 20 th century for the treatment of gout.Giround discovered the anthelmintic activity of piperazine, synthesized by Cloez in1853, fortuitously in 1942; the same effect was observed by Biosmare in 1948 andconformed by Bayared in 1949. Structural modification of this molecule in the searchfor effective filaricidal resulted in diethyl carbamazine synthesized by Kishner et al in1946 and studied pharmacologically by Hewitt et al in 1947. Clinical studies haveshown that the drug is highly effective against both ascaris lumbricoides andenterobius (oxyuris) vermicularis.CHEMISTRYPiperazine is a six member cyclic secondary diamine with the nitrogen in the1, 4 - position. It can also be called diethelenediamine for convenience its molecularformula can be written C 4 H 10 N 2 , and structural formula shown as under (I).HNNH( I )PHYSICAL PROPERTIESPiperazine is soluble in water and ethanol, but insoluble in ether. An aqueoussolution reacts strongly alkaline, the P ka being 9.8.It occurs in the form of hygroscopicplates M.P. 104 0 C and B.P. 140 0 C. It is available as the hexahydrate which containsabout 44% of base and in addition, as various salt such as citrate C 24 H 46 N 6 O 14, M.P.182 0 -187 0 C, adipate C 10 H 20 N 2 O 4, M.P. 256 0 -257 0 C, phosphate, calcium acetate andtartrate.ECONOMIC ASPECTSTotal production of piperazine is about 3 million lb/yr. Most of this isconverted to one of the salts since these are widely used as animal anthelmintics andare more easily administrated in this form.16

Introduction of piperazine derivativesSTORAGE & HANDLINGAnhydrous piperazine should be stored in a dry, airconditioned building at atemperature below 60 0 F. On contacting oxygen, piperazine will darken in colour to adeep yellow after a long period of time. When anhydrous piperazine is exposed to theatmosphere, it will pick up moisture and will tend to cake and darken in warmwhether.HEALTH & SAFETYAnhydrous piperazine itself has a low acute oral toxicity. However theinvestigation of large amounts should be avoided and in case where large amountshave been swallowed, vomiting should be induced and medical attention obtainedpromptly. Piperazine exhibits a sensitizing potential so that pronged exposure to smallquantities or a short exposure to a single massive quantity should be avoided.Because of its alkalinity, piperazine can cause serious eye damage. Whenpiperazine has accidentally been introduced into the eye flushing for 15 minute withrunning water is recommended as the first-aid measure. Piperazine exhibits a highvapours pressure and should be handled in well-ventilated areas only.PHARMACOLOGICAL EFFECTThe effects of piperazine on ascaris have been investigated intensively. Thegross effect is a paralysis of muscle that results in expulsions of the worm byperistalsis. Affected worms recover if incubated in a saline medium at 37 0 C. Furtherstudies have shown that piperazine blocks the response of ascaris muscle toacetylchloline, an action that is much weaker in skeletal muscle preparations. It hasbeen proposed that piperazine acts on ascaris muscle by altering the permeability ofthe cell membrane to ions that are responsible for the maintenance of the restingpotential. Piperazine also inhibits production of succinate by Ascaris at concentrationsthat resulting paralysis and bioclade of the stimulatory effects of acetylcholine.Orally administrated piperazine is almost devoid of pharmacological activity.Intravenous administration results in a transient fall in blood pressure. Lethal dosescause convulsions and respiratory depression. A large number of substitutedpiperazine derivatives exhibit anthelmintic activities.Various derivatives have found actual or potential use as antihistamines,hypertension, anesthetic, analgesic epilepsy, anticonvulsant, antispasmodic, burnshock and hemorrhagic shock. Other application of piperazine and its derivatives17

Introduction of piperazine derivativesexcept medicine was rubber antioxidants, corrosion inhibitors, additives, wettingemulsifying, cosmetic, dyeing industry, resin, polymers, synthetic fibers andanalytical reagent.SYNTHETIC ASPECTPreparation of piperazine at atmospheric pressure; diethylene triamine washeated with Raney nickel under various experimental conditions. The results of theseexperiments are tabulated below. In all cases ammonia was evolved and piperazineformed according to the reaction. A temperature at about 150°C or somewhat higherwas found to be most suitable for the reaction (II).H NCH 2CH 2NH 2NiH2CHNH2CNH+ NH3CH 2CH 2NH 2( II )CH2CH2Autoclave method of piperazine; The autoclave was charged with 150 gm ofN-(2-hydroxy ethyl)-ethylene diamine in 200 ml of dioxane 5-30 gm of catalyst wasadded, and reaction was carried out for three hours at a temperature in the range 200-300°C. The reaction mixture filtered from catalyst was distilled; dioxane-waterazeotrope distilled at 87°C, then dioxane at 100-103°C, and finally piperazine at 140-150°C. Raney nickel appeared the catalyst at choice; copper chromium oxide,activated alumina, silica gel, cupric oxide and iron, were intermediate ineffectiveness. 1-9THERAPEUTIC IMPORTANCER. Rastogi et al 10 prepared N-(2-substituted-ethyl)-N’-aryl piperazine (III) aspotential antihookworm agents.R1ROCH2CH2NN( III )18

Introduction of piperazine derivativesN. Serradji at eal 11 have been synthesized a variety of analogues 1-[4-methoxy-3,5-dimethyl benzyl]-4-[3-(ethyl amino)-2-pyridyl]piperazine hydrochloride(IV) and evaluated for their anti HIV activity.H3COCH3NHCH 2CH3H3CNNN. HCl( IV )L-Romero et al 12 and S. Ali et al 13 have been synthesized various piperazinesderivatives and evaluated its antiviral activity.R. B. Petigara et al 14 synthesized various N 1 -N 4 -disubstituted piperazinederivatives in which the N 1 substitutents are 3,4,5-trimethoxy benzoyl alkyl (V) andscreened for CNS activity, majority of the compounds produced CNS depressanteffects as shown by gross observation of intact animals and confirmed by motoractivity studies in some conditional avoidance behavior.H 3 CO3 COH 3 CO3 COANNHH 3 CO3 CO( V )S. K. Saxena et al 15 synthesized piperazine derivatives (VI) and B. M.Khadilkar et al 16 (VII) showed best CNS depressant, anti-inflammatory, diureticactivities.19

Introduction of piperazine derivativesO 2 ) 3H 3 (CH CON NClH 3 COA HN3 CONHH 3 CONH 2( VI )H 3 COCH 3RNO(CH 2 ) 3NNCOCl( VII )R. C. Tripathi et al 17 have been synthesized piperazine derivatives andevaluated its hypotensive and CNS depressant activities.Pyrazole derivatives (VIII) and (IX) containing substituted piperazine nucleuspossess antitumor activity evaluated by A. Ejima and S. Ohsuki. 18MeMeNNNNHC=CC=CHCH2NCH2NClCl( VIII )MeClNNNNNNN CO(CH 2)2 H N NC=CH CH2NN( IX )ClFCl20

Introduction of piperazine derivativesThe effect of (X) hydrochloride on blood pressure of cat was studied by B. M.Khadilkar et al 19 for intracerebroventricular administration at the dose of 50-µg/kgweights. The fall in B.P. was so rapid that cat died within 15 minutes.OOHOHNON( X )NRS. K. Agrawal et al 20 prepared 1-(3-carboxyphenoxy)-3-(N 1 -N 4 -phenypiperazinyl) -propane (XI), some of these compounds show potent CNSdepressant, hypotensive and α-adrenoceptor blocking activities.O(CH 2 ) 3NNHOOC( XI )U. V. Kargaonkar et al 21 have prepared ethyl-8-[4-(3-chlorophenyl)-1-piperazinyl methyl]-2-oxocoumarin-4-acetate (XII) as most effective antiinflammatoryagents. Analgesic and anti-inflammatory activities of piperazinesreported by several research workers. 22-27 OCOOC2H5OONN( XII )ClPreparation and activity against plasmodium berghei of compound 1-(4-methoxycinnamoyl)- 4 - [5-(4-chloro/bromo)phenyl-4-oxo-2-oxazin-2-yl] - piperazine(XIII) were described by Herrin and his co-workers. 28 Some nitrogen containing21

Introduction of piperazine derivativesheterocycles found to posses high antimalarial activity, which was described by F. S.Mikhalitsym et al. 29Br/ClONNOON(XIII)OCH 3L. C. Meurer and his coworkers 30 synthesized alkyl & halo substituted 8-(1-piperazinyl)imidazol [1,2-α]pyrazine and studied their hypoglycemic activity. In thesederivatives some compounds showed potent hypoglycemic activity. Varieties ofhypoglycemic agents contained with piperazine moiety were also assessed by severalinvestigators. 31,32Some piperazine derivatives are showed a useful activities like as brainprotectant 33 , diagnosis of schizophrenia 34 , neurokinine 35,36 , serration antagonistreceptors 37-39 , heart muscle receptor 40 , and cholesterol reducing agents 41 , HIV-Iinhibitors 42,43 , dopamine transporter 44-46 , sorbitol dehydrogenase inhibitor 47-49 ,spermicidal agent 50 . Besides the anathematic application of piperazine 51-53 ,anesthetic 54 , antiparkinson 55 , anticonvulsant 56-58 , antidepressant agents 59 ,antipshycotic 60-61 , antiallergic 62-64 , antiulcer 65 , insecticide 66 , antiparasitics 67 , andnormolipemic hypoglycemic & hypotriglyceridemic activity. 685-{[4- [4- (Fluorophenyl) -1- piperazinyl] - butyryl] amino}-5H-dibenzo[a,d]cyclohepene] (XIV) selectively for cardiac tissue over vascular tissue, therebyconferring antianginal activity without an effect on blood pressure by M. Kurokawaet. al. 6922

Introduction of piperazine derivativesNHCO(CH 22 ) 3) 3NNF(XIV)G. R. Brown 70 synthesized 1 - (Arylsulfonyl) - 4 - {[1-(4-pyridyl)piperazine-1-yl] carbonyl}piperazines and analogs (XV) are useful as oxidosqelenecyclase inhibitors. 2-Piperazine-1-acetic acid derivatives are used as plateletaggregation inhibitors and antithrombotics 71 , piperazinyl ethyl indazoles ascalmodulin inhibitors 72 and tryptase inhibiting alkynediol piperazine carboxylicesters. 73ONNNCNNSBrO(XV)OS. Paris et.al. 74 synthesized pyrrolo[3,2,1-i,j]quinoline (XVI) and documentedas potential therapeutic application in asthma.NR CH2CH2 N N NMeMeR'(XVI)[(Piperazine)alkylthio]pyridine (XVII) was recommended for the controlhelicobacter pybri bacteria by G. Hanauer and his co-workers. 75NNN N S N N(XVII)Me Me SNH NH23

Introduction of piperazine derivativesS. Seshadri et. al. 76 prepared dimeric products (XVIII) and (XIX) ofdithioacetals with piperazine showed moderate to significant activity. Thesecompounds also show better activity against gram negative bacteria as compared togram positive bacteria.H 3 C CO HN SO 2 N C N N C N SO 2NHCOCH 33 CO HN SO 2SO 2NHCOCH 3SCH 3 SCH 3SCH 3 SCH 3(XVIII)H 2 N SO 2NCNNCNSO 2NH 2SCH 3 SCH 3(XIX)S. J. Brickner et. al. 77 prepared potent, synthetic oxazolidinones (XX) which iscurrently in clinical development for the gram positive bacterial infections caused bystrains of Staphylococci, Streptococci & Enterococci. The in vitro and in vivoactivities of above compound, against representative strains are similar to these ofvancomycin. These compounds demonstrate potent in vitro activity againstmycobacterium tuberculosis.OHO CNN(XX)FNHONHOCCH324

Introduction of piperazine derivativesSome quinazolinone derivatives containing substituted piperazines (XXI)found to posses strong antibacterial activity. 78-84 Substituted piperazinyl-phenyloxazolidionederivatives used as antibacterial agents, which showed MIC of 0.5 µg/mlagainst S. auresas by G. D. Cung et. al. 85OCOOH COOHR' R'RNN(XXI)NR1R17-[(4- Substituted phenylpierazine-1-yl) - alkoxyl]- 4 -methylchromene-2-ones(XXII) as potential atypical antipsychotics synthesized and evaluated by S. H.Bhosale and his co-workers. 86CH3R1R2OOO(CH2)nNNR3(XXII)N 1 - (2- Substituted-4-nitrophenyl)-N 4 -(2,3 - disubstitutedpropyl) - piperazines(XXIII) as useful antifungal agent prepared and characterized by G. L. Talesara et.al. 87 N NO 2 N CH 2 CHCH 2R'X(XXIII)R25

Introduction of piperazine derivativesPreparation and biological evaluation of (5-methyl-1H-indol-2-yl)-4-methylpiperazine-1-yl)-methanone(XXIV) as potent human histamine H 4 antagonists by J.H 3 CC N N CHD. Venable and his co-workers. 88 NHO3(XXIV)N-{4-[4-(2,3-Dichlorophenyl)-piperazine-1-yl]trans-but-2-enyl}-4-pyridine-2-yl-benzamide (XXV) as selective probes with high affinity for the dopamine D3receptor has been prepared by P. Grundt et. al. 89Cl ClCl ClOC OCNH NHNNNNNN(XXV)N-(2- Chloro-6-methylphenyl)- 2 -(6-(4-(2- hydroxyethyl)- piperazine-1-yl - 2 –methyl pyrimidine-4-ylamino)thiazole-5-carboxamide (XXVI), a dual Src/Abl kinaseinhibitors with potent antitumor activity in preclinical assays has been synthesizedand discovered by L. J. Lombardo et al. 9026

Introduction of piperazine derivativesCH3CH3CH3CH3NHCl ClOSNNHNNNN(XXVI)OH OHSeveral investigators synthesized varieties of new compounds withpiperazine moiety and found their antimicrobial activities such as antifungal andantibacterial. 91-101Flunarizine (brand name sibelium) {1-cinnamyl-4-[(4',4"-diflurodiphenyl)-methyl]-piperazine}(XXVII) was discovered at Janssen Pharmaceutical in 1967.Flunarizine is a drug classified as a calcium channel blocker. Flunarizine is a selectivecalcium entry blocker with calmodulin binding properties and histamine H1 blockingactivity by W. K. Amery. 102 It is effective in the prophylaxis of migraine, occlusiveperipheral vascular disease, vertigo of central and peripheral origin, and as anadjuvant in the therapy of epilepsy. It may help to reduce the severity and duration ofattacks of paralysis associated with the more serious form of alternating hemiplegia.Potent visodilater improve cerebral blood flow reduce duration and incidences ofmigraine attack by J. M. Van Nueten. 103FNNF(XXVII)27

Introduction of piperazine derivativesLomerizine{1-(2''',3''',4'''-trimethoxybenzyl)-4-[(4',4"-diflurodiphenyl)-Methyl]-piperazine}(XXVIII) is a calcium channel blocker with antimigraine properties. 104-108FNNH 3 COF(XXVIII)H 3 CO OCH 3Thus the important role displayed by piperazine derivatives for varioustherapeutic and biological activities prompted us to synthesize some arylamide,sulphonamides, Mannichbases, Schiff’s bases, 4-thiazolidinones, 2-azetidinones, 5-oxo-imidazolines etc. bearing piperazine moiety in order to active compounds havingbetter biological activities as described in the following parts.STUDIES ON PIPERAZINE DERIVATIVESPART – I : STUDIES ON ARYLAMIDEPART- II : STUDIES ON SULPHONAMIDESPART - III : STUDIES ON MANNICH BASESPART- IV : STUDIES ON SCHIFF’S BASESPART- V : STUDIES ON 4-THIAZOLIDINONESPART- VI : STUDIES ON 2-AZETIDINONESPART- VII : STUDIES ON 5-OXO-IMIDAZOLINES28

Studies on ArylamideSTUDIES ON ARYLAMIDEINTRODUCTIONThe characteristic group present in the simple carboxylic amide is CONH 2 .They are the acyl substitution products of ammonia. Many natural products areamides (-CO-NH-), urea (-NH-CO-NH-), and diamides (-CO-NH-CO-NH)derivatives of carbonic acid. The peptides and proteins are linear structure of cyclicpolyamides. The alkaloids of pepper, piperidine and chavicine are N-substitutedamides of unsaturated acid. N-isobutyl amides of certain highly unsaturated aliphaticacids occur in plants, shows insecticidal activity. 109 Amides derived frompolyacetylenic acid have been isolated from certain fungi. 110SYNTHETIC ASPECT:Various methods for the synthesis of aryl amides are described inliterature. 111-117 Marayama, Tatsuya, Suzuki Onda 118 have synthesized arylamide (I) asunder.PhOHClN H 2NH+ClNONClPyridineHOPhNH( I )NNNHOMECHANISM..R NH 2+R 1OClHR N +HO -RClHR N +HOR'+ Cl-HO-H + + B.HCl 29RNR'

Studies on ArylamideTHERAPEUTIC IMPORTANCEAmides, aryl amides, heterocyclic aryl amides showed widely useful aspharmacologically activities. The biological activities of aryl amide derivatives havebeen reported as under.1. Anticonvulsant 1192. Herbicidal 1203. Cardiotonic 121122, 1234. Antimicrobial5. Analgesic 1246. Antiulcer 1257. MAO inhibitor 1268. Anticancer 127,1289. Antiinflammatory 12910. Anti-HIV 130131, 13211. Sodium channel blockersA. K. Mallams 133 has reported arylamide derivatives as antitumor agent. Moreover S. J. Laulloo et al 134 and J. Hazarika 135 have prepared some new biologicallyactive arylamide derivatives and reported them as antimicrobial agents. DhanakDushyant et al. 136 have synthesized arylamide (II) useful as urotensin-II antagonist.HNClNHOClClOOClHNNHSONHNO( III )( II )E. J. Sanderson Philip et al 137 (III) have synthesized aryl amides and studiedtheir biological activity. M. B. Anthony et al. 138 have reported aryl amide derivativesas antiulcer agents. J. E. Foster et al. 139 have synthesized some new amide derivativesas potent anticonvulsant. A. R. Mulik et al. 140 have studied some aryl amides showsantibiotic activity. G. Bridge et al. 141 have screened arylamides as anti-HIV agent. L.Bettineti and co-workers 142 have prepared arylamides as antibacterial agents. D. W.30

Studies on ArylamideHobbs et al. 143 have designed some amides and reported them as MCH-receptorantagonist.S. Tabuchi et al. 144 have screened arylamide derivatives as novel potentantagonist of human neuropeptide YY5 receptor. J. H. Chan 145 have recordedsubstituted benzophenone arylamide derivatives as inhibitor reverse transcriptase. L.Pieters et al. 146 have synthesized new diazene carboxamides (IV) as anticancer. N. J.Anthony and co-workers 147 have investigated amides as anti-HIV. G. Chen et al. 148have reported aryl amides (V) as antitumor agents.ONHNNFFFONHCF 3CH 3NCH3( IV )FFNNHF( V )CONTRIBUTION FROM OUR LABORATORYSome new arylamide derivatives bearing benzimidazol (VI) moiety wereassessed by H. H. Parekh et al. 149 and evaluated its antimicrobial activity. A. R. Parikhet al. 150-153 have synthesized new arylamide derivatives of (VII), (VIII) and reportedthem as antimicrobial agents.RNNNH 2N ONNNH 2OH NOSNHNH NHRN( VI ) R( VII )OH ( VIII )OV. H. Shah et al. 154 (IX) have synthesized some new aryl amide and evaluatedits antimicrobial activity. V. N. Patoliya et al. 155-158 (X-XI) have synthesized andevaluated its antimicrobial activity.31

Studies on ArylamideD. M. Purohit et al. 159 have reported new aryl amides in Piperazine moleculesas a antimicrobial agent (XII).OOOOOOOONNRNNRNNRNNRC H 3OHSNCl(IX)H 2CH 3ONNNHOHOHOOCOR(X)OOCOOHRC H 3OO N NH RO(XI)NON NH RNNHCH 3N CH 3NNNHOCl(XI)Cl(XII)RIn the past years, considerable evidence has been accumulated to demonstratethe pharmacodynamic and chemotherapeutic activities of amide derivatives. Tofurther assess the potential of such type of compounds, the synthesis have beencarried out which have been described as under.SECTION-I: SYNTHESIS AND BIOLOGICAL SCREENING OF 1-AROYL-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.SECTION-II: SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-AROYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.32

Studies on ArylamideSECTION - ISYNTHESIS AND BIOLOGICAL SCREENING OF 1-AROYL - 4 - [(4', 4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Aryl amide represents one of the important classes of compounds, with anintension of preparing the compounds possessing better therapeutic activity such asantimalarial, anthalmintics, anticonvulsant, antihistamine, anti-inflammatory etc. Inview of getting 1-aroyl-4-[(4',4"-difluorodiphenyl)-methyl]- piperazines of Type (I)have been synthesized by the condensation of 1-(H)-4-[(4',4"-difluorodiphenyl)-methyl]-Piperazine with aroyl chloride.FNNORFType-IR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no-A.33

Studies on ArylamideIR SPECTRAL STUDY OF 1 - (4"'- METHOXYBENZOYL) - 4 - [(4', 4" -DIFLUORODIPHENYL) - METHYL] - PIPERAZINE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration Frequency in cm -1 Ref.mode Observed ReportedC-H str.(asym.) 2964 2990-2850 474AlkaneC-H str. (sym.) 2860 2880-2860 "C-H def. (asym.) 1462 1470-1435 "C-H def. (sym.) 1369 1390-1370 "C-H str. 3057 3090-3030 "Aromatic C=C str 1500 1600-1450 "C-H i.p. (def.) 1278 1300-1100 "Piperazine C-N str. 1319 1360-1310 475Halide C-F str. 711 800-600 "Ether C-O-C 1219 1260-1200 "ArylamideC-N str. 1155 1220-1020 "C=O str. 1637 1700-1630 "34

Studies on ArylamideNMR SPECTRAL STUDY OF 1 - (4"'- METHOXYBENZOYL) - 4 - [(4', 4" -DIFLUORODIPHENYL) - METHYL] - PIPERAZINE.OFghedNcbg'h'fNe'd'c'b'OCH 3ai'j'ijFInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.20-2.35 4H doublet C-H (ee’)2 3.31-3.65 4H doublet C-H (dd’)3 4.15 3H singlet Ar-OCH 3 (a)4 5.23-5.27 1H singlet C-H (f)5 6.90-6.92 4H singlet Ar-H (gg’, jj’)6 7.28-7.29 8H singlet Ar-H(hh’, ii’, bb’, cc’)35

Studies on ArylamideMASS SPECTRAL STUDY OF 1 - (4"'- METHOXYBENZOYL) - 4 - [(4', 4" - DIFLUORODIPHENYL) - METHYL] -PIPERAZINE.36

Studies on ArylamideMASS FRAGEMENT STUDY OF 1-(4"'-METHOXYBENZOYL)-4-[(4', 4" -DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.HNN+oOCH 3OOCH 3+oFm/z = 96+oFm/z = 288FNm/z = 220+oNHm/z = 108O C H 3+oN H 2F+om/z = 151FONH 2m/z = 219FFNOFNOCH 3OH 3 C NH 3+om/z = 422NN+oCm/z = 275FFm/z = 316FCH 3F+oNNOO+oCH 3NH+oON+oOm/z = 207m/z = 328H NH 3 CCH 3Fm/z = 204m/z = 86F37

Studies on ArylamideREACTION SCHEMEFFOHTolueneSOCl 2RefluxFFClPiperazineTolueneRefluxFNNHFPyridineFROClNNORFType - IR = Aryl38

Studies on ArylamideEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1-AROYL - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.[A] Synthesis of 1-chloro-1-[(4',4"-difluorodiphenyl)-methane:A mixture of 1-(4',4"-difluorodiphenyl)methanol (2.20 gm,0.01M) in Toluene(25 ml) with thionyl chloride (1.3 gm, 0.011M) was stirring with at room temp. for 2hrs, than after the reaction mixcture refluxed 110-112 o C for 8 hrs. Toluene is distilledout completely and remained product is oil form. B.P.321°C; Yield: 82.86 %.(C 13 H 9 ClF 2 : Required: C: 65.42; H: 3.80; Cl: 14.89; Found: C: 65.40; H: 3.77; Cl:14.88 %)[B] Synthesis of 1 -[(4',4"-difluorodiphenyl)-methyl]-piperazine:A mixture of 1-chloro-1-[(4',4"-difluorodiphenyl)-methane(2.38gm,0.01M),anhydrous piperazine (3.44gm, 0.04M), Toluene (25 ml) was heated under reflux in aoil bath for 8-10 hours. The reaction mixture is cool at room temp. Filter it and filtratewash with water (25 ml) and separate layers. Take toluene layer and add water (25ml) than acidify with Con. HCl about 2.0 pH. and separate layers. Take aqueous layerand basify with caustic lye about 13.0 pH. Filter the product and wash with waterdried and crystallized from methanol. M.P.92°C; yield 85.72%. (C 17 H 18 F 2 N 2 :Required: C: 70.83; H: 6.25; N: 9.72; Found: C: 70.79; H: 6.23; N: 9.70 %).[C] Synthesis of 1-(4"'-methoxybenzoyl)-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine(1e):A mixture of 1-(H)-[(4',4"-difluorodiphenyl)-methyl]-piperazine (2.88 gm,0.01M) and 4-methoxybenzoyl chloride (1.70gm, 0.01M), pyridine(10 ml) was heatedon an oil bath at 120 0 c for 5-6 hours. The reaction mixture was cooled and poured into crushed ice, neutralized with diluted hydrochloric acid, filter it and washed withwater. The isolated product was crystallized from methanol. M.P. 129°C; yield63.71%.( C 25 H 24 O 2 N 2 F 2 : Requried: C:71.08; H:5.68; N:6.63; Found: C:71.04; H:5.60;N:6.61%).Similarly, other aryl amides were synthesized. The physical data are recordedin Table no-1.39

Studies on Arylamide[D] Biological Screening of 1 - aroyl - 4 - [(4',4"-difluorodiphenyl) -methyl] -piperazines.All the compounds have been evaluated for their biological screeningrepresented in Graphical chart no-1.(a) Biological screening:It was carried out by cup-plate diffusion method 476 which has been describedas under.(I) Antibacterial Screening 476The purified products were screened for their antibacterial activity using cupplateagar diffusion method. The nutrient agar broth prepared by the usual methodwas inoculated aseptically with 0.5 ml of 24 hr. old subcultures of Bacillus subtillis,Bacillus cerus, Escherichia coli, Enterobacter aerogen in separate conical flasks at40-50 o C and mixed well by gentle shaking. About 25 ml content of the flask waspoured and evenly spreaded in a petridish (13 cm diameter) and allowed to set for 2hrs. The cups (10 mm diameter) were formed by the help of borer in agar medium andfilled with 0.05ml (50μg) solution of sample in DMF.The plates were incubated at 37 o C for 24 hrs. and the control was alsomaintained with 0.05ml of DMF in a similar manner and the zone of inhibition of thebacterial growth were measured in millimeter and recorded in Part-I, section-I, pageno-42, Table No- A.(II)Antifungal Screening 476Aspergillus niger was employed for testing antifungal activity using cup-plateagar diffusion method. The culture was maintained on sabourauds agar slantssterilized sabourauds agar medium was inoculated with 72 hrs. old 0.5ml suspensionof fungal spores in a separate flask.About 25 ml of the inoculated medium was evenly spreaded in a Petri dish(13cm diameter) and allowed to set for 2 hrs, the cups (10mm diameter) werepunched. The plates were incubated at 30 o C for 48 hrs.After the completion of incubation period, the zone of inhibition of growth inthe form of diameter in mm was measure. Along the test solution in each Petri dishone cup was filled up with solvent, which acts as control. The zones of inhibition oftest solution are recorded in Part-I, section-I, page no-42, Table No- A.40

Studies on ArylamideBIOLOGICAL SCREENINGMethod : Cup-Plate 476Gram positive bacteria : Bacillus subtillisBacillus cerusGram negative bacteria : Escherichia coliEnterobacter aerogenFungi : Aspergillus nigerConcentration : 50µg/mlSolvent : Dimethyl formamideStandard drugs : AmpicillinChloramphenicolNorfloxacinGreseofulvin.The biological screening was compared with standard drug viz Ampicillin,Chloramphenicol, Norfloxacin, and antifungal activity was compared with vizGreseofulvin. The inhibition zones were measured in mm. The zones of inhibition thatdisplayed by standard drugs are recorded in part-I, section-I, page no-42, Table no-A.41

Studies on ArylamideTABLE NO - A : ANTIMICROBIAL ACTIVITY ZONE OF INHIBITION OF STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. nigerAmpicillin (50 µg/ml) 23 22 21 19 --Chloramphenicol(50 µg/ml) 22 23 21 20 --Norfloxacin (50 µg/ml) 24 21 23 22 --Greseofulvin (50 µg/ml) -- -- -- -- 2342

TABLE NO-1: PHYSICAL CONSTANTS OF 1-AROYL - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Studies on ArylamideSr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.1a C 6 H 5 - C 24 H 22 ON 2 F 2 392 184 88.72 7.14 7.101b 2-CH 3 -C 6 H 4 - C 25 H 24 ON 2 F 2 406 122 74.52 6.89 6.851c 4-CH 3 -C 6 H 4 - C 25 H 24 ON 2 F 2 406 211 74.26 6.89 6.801d 2-OCH 3 -C 6 H 4 - C 25 H 24 O 2 N 2 F 2 422 121 63.87 6.63 6.601e 4-OCH 3 -C 6 H 4 - C 25 H 24 O 2 N 2 F 2 422 129 63.71 6.63 6.611f 2-Cl-C 6 H 4 - C 24 H 21 ON 2 F 2 Cl 426 134 73.52 6.56 6.521g 2-NO 2 -C 6 H 4 - C 24 H 21 O 3 N 3 F 2 437 172 60.11 9.61 9.571h 3-NO 2 -C 6 H 4 - C 24 H 21 O 3 N 3 F 2 437 152 59.09 9.61 9.551i 4-NO 2 -C 6 H 4 - C 24 H 21 O 3 N 3 F 2 437 192 60.99 9.61 9.501j 3,4-(OCH 3 ) 2 -C 6 H 3 - C 26 H 26 O 3 N 2 F 2 412 187 79.55 6.19 6.1543

Studies on ArylamideGRAPHICAL CHART NO-1: BIOLOGICAL SCREENING OF 1 - AROYL - 4 - [(4', 4"- DIFLUORODIPHENYL) - METHYL] -PIPERAZINES.30ZONE OF INHIBITION IN mm25201510501a 1b 1c 1d 1e 1f 1g 1h 1i 1j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 15 13 22 20 24 16 23 12 19 23 23 22 24 0B.ce rus 14 23 20 16 22 14 16 21 19 15 22 23 21 0E .coli 20 16 19 23 15 21 19 17 18 20 21 21 23 0E .aerogen 19 13 21 12 13 19 15 18 16 22 19 20 22 0A.niger 21 16 15 23 22 21 16 20 18 19 0 0 0 2344

Studies on ArylamidePART-ISECTION – I : BIOLOGICAL SCREENING STUDY OF 1-AROYL - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger1c-(22) 1b-(23) 1a-(20) 1a-(19)1a-(21)1e-(24) 1c-(20) 1d-(23) 1c-(21) 1d-(23)1g-(23) 1e-(22) 1f-(21) 1f-(19) 1e-(22)1j-(23) 1h-(21) 1j-(20) 1h-(18) 1f-(21)1j-(22)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 2345

Studies on ArylamideSECTION – IISYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-AROYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.Aryl amide represents one of the important classes of compounds, with anintension of preparing the compounds possessing better therapeutic activity suchas antihistamine, anti-inflammatory, anticonvulsant, antipyretic, analgesic etc. In viewof getting 1-N-aroylamino-4-[(4',4"-difluorodiphenyl)-methyl]- piperazines of Type(II) have been synthesized by the condensation of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-Piperazine with aroyl chloride.FFNN N+NNHROFFType-IIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no-A.46

Studies on ArylamideIR SPECTRAL STUDY OF 1 - N -[(4"'-METHOXYBENZOYL)-AMINO] - 4 -[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).TypeVibrationFrequency in cm -1mode Observed ReportedRef.C-H str.(asym.) 2989 2990-2850 474AlkaneC-H str. (sym.) 2894 2880-2860 "C-H def. (asym.) 1456 1470-1435 "C-H def. (sym.) 1384 1390-1370 "C-H str. 3066 3090-3030 "Aromatic C=C str 1490 1600-1450 "C-H i.p. (def.) 1213 1300-1100 "Halide C-F str. 703 800-600 475Piperazine C-N str. 1315 1360-1310 "Ether C-O-C str. 1276 1260-1200 "ArylamideC-N str. 1083 1220-1020 "C=O str. 1677 1700-1630 "Sec. amine N-H str. 3359 3500-3100 "47

Studies on ArylamideNMR SPECTRAL STUDY OF 1 - N -[(4"'-METHOXYBENZOYL)-AMINO] -4 -[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.FhifeNdNHOh'i'gNf'e'cc'j'jbb'k'FkOCH3aInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.40-2.46 4H doublet C-H (ff’)2 2.64-2.67 4H doublet C-H (ee’)3 3.80 3H singlet Ar-OCH 3 (a)4 5.30 1H singlet C-H (g)5 6.93-6.96 4H triplet Ar-H (hh’, kk’)6 7.18-7.27 2H triplet Ar-H (bb’)7 7.39-7.48 4H doublet Ar-H (ii’, jj’)8 7.81-7.83 2H doublet Ar-H (cc’)9 8.27 1H singlet N-H (d)48

Studies on ArylamideMASS SPECTRAL STUDY OF 1 - N - [(4"'-METHOXYBENZOYL) - AMINO] - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.49

Studies on ArylamideMASS FRAGEMENT STUDY OF 1 - N - [(4"'-METHOXYBENZOYL) - AMINO] - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.F+oF+oOCH 3OCH 3+oH NNm/z = 208FN H 2NNm/z = 303FONHNNHm/z = 235+oH NNHm/z = 86+oF+oO NH 2m/z = 151FOCH 3FN H 2m/z = 219FFN+oCH 3NH 3Cm/z = 275+oFONHNm/z = 437FONHNOCH 3Nm/z = 331FFm/z = 96+oOOCH 3NHm/z = 166+oNH 2Fm/z = 204+oFOOCH 3NHNNm/z = 343OFNH+oNCH 3+oCH 3m/z = 22250

Studies on ArylamideREACTION SCHEMEFNNHFFNaNO 2 + HCl0-5 0 CN N NOFFLiAlH 4N N NH 2OFFR ClPyridineON N NHRType - IIFR = Aryl51

Studies on ArylamideEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-AROYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.[A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:A mixture of 1-[(4',4"-difluorodiphenyl)-methyl]-piperazine (8.6 gm, 0.03M)in 50 ml of ice cold water containing 24 ml of diluted HCl is nitrosated with 2.1 gmNaNO 2 in 10 ml water. The reaction mix is made alkaline by the addition of NaOHSolution and an oily layer forms. The oily product is separated and crystallized from amix of 5 ml ethyl acetate - 70 ml n-heptane. The resultant solid is recystallized from amixture of 2-propanol and hexane, to give 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine. M.P.153-155°C; Yield: 80.56 %. (C 17 H 17 N 3 F 2 O; Required: C:64.34; H: 5.40; N:13.24; Found: C: 64.30; H: 5.37; N: 13.22 %).[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:A mixture of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine (10 gm,0.03 M) in 140 ml of anhy. ether and 5 ml of benzene is added drop wise to asuspension of 1.9 gm of Lithium aluminium hydride in 140 ml of ether. The reactionmixture is stirred for 1 hrs at room temperature and then refluxed and stirred for 2 hrs.The reaction mixture is cooled in an ice bath and excess Lithium aluminum hydride isdecomposed by the addition of ethyl acetate. The reaction mixture is hydrolyzed bydrop wise addition of 2 ml of water, 2ml of 20 % NaOH solution. The inorganic saltsare filtered and washed with ether. The filtrate is dried over sodium sulphate. Thesolvent is evaporated, the residue is dissolved in benzene and the solvent isevaporated once again to give 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine. M.P.126-129°C; Yield: 57.72%. (C 17 H 19 F 2 N 3 ; Required: C: 67.31; H:6.31; N: 13.85; Found: C: 67.27; H: 6.29; N: 13.83 %).[C] Synthesis of 1 - N - [(4"'-methoxybenzoyl)-amino] - 4 - [(4',4"-difluorodiphenyl)-methyl]-piperazine(2e):A mixture of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine (3.03gm,0.01M) and 4-methoxybenzoyl chloride (1.70gm, 0.01M), pyridine(20 ml) was heatedon an oil bath at 120°C for 5-6 hours. The reaction mixture was cooled and poured in52

Studies on Arylamideto crushed ice, neutralized with diluted hydrochloric acid, filter it and washed withwater. The isolated product was crystallized from ethanol. M.P. 169°C; yield 68.71%.(C 25 H 25 O 2 N 3 F 2 ; Requried: C: 68.64; H: 5.76; N: 9.60; Found: C: 68.61; H: 5.74;N:9.58 %).Similarly, other aryl amides were synthesized. The physical data arerecorded in Table no-2.[E] Biological screening of 1-N-aroylamino-4-[(4',4"-difluorophenyl)-methyl]-piperazines:Biological screening was carried out as described in Part-I, Section-I, page no.40. The zones of inhibition of test solutions are recorded in Graphical Chart no-2.53

Studies on ArylamideTABLE NO-2: PHYSICAL CONSTANTS OF 1-N-AROYLAMINO - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.2a C 6 H 5 - C 24 H 23 ON 3 F 2 407 172 85.72 10.31 10.292b 2-CH 3 -C 6 H 4 - C 25 H 25 ON 3 F 2 421 157 76.52 9.97 9.962c 4-CH 3 -C 6 H 4 - C 25 H 25 ON 3 F 2 421 192 74.56 9.97 9.962d 2-OCH 3 -C 6 H 4 - C 25 H 25 O 2 N 3 F 2 437 182 63.67 9.60 9.582e 4-OCH 3 -C 6 H 4 - C 25 H 25 O 2 N 3 F 2 437 169 68.71 9.60 9.582f 2-Cl-C 6 H 4 - C 24 H 22 ON 3 F 2 Cl 441 148 77.53 9.51 9.502g 2-NO 2 -C 6 H 4 - C 24 H 22 O 3 N 4 F 2 452 176 65.19 12.38 12.362h 3-NO 2 -C 6 H 4 - C 24 H 22 O 3 N 4 F 2 452 198 57.59 12.38 12.362i 4-NO 2 -C 6 H 4 - C 24 H 22 O 3 N 4 F 2 452 183 64.54 12.38 12.362j 3,4-(OCH 3 ) 2 -C 6 H 3 - C 26 H 27 O 3 N 3 F 2 467 202 78.35 8.99 8.9754

Studies on ArylamideGRAPHICAL CHART NO- 2: BIOLOGICAL SCREENING OF 1-N-AROYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.30ZONE OF INHIBITION IN mm25201510502a 2b 2c 2d 2e 2f 2g 2h 2i 2j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 22 15 17 23 14 21 15 19 22 24 23 22 24 0B.cerus 20 15 21 19 20 22 15 23 22 18 22 23 21 0E .coli 19 21 16 20 16 18 23 19 20 21 21 21 23 0E .aerogen 17 19 16 20 22 17 21 18 14 22 19 20 22 0A.niger 18 22 18 21 17 15 22 20 19 23 0 0 0 2355

Studies on ArylamidePART-ISECTION - II : BIOLOGICAL SCREENING STUDY OF 1-N-AROYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger2a-(22) 2a-(20) 2b-(21) 2b-(22) 2b-(22)2d-(23) 2c-(21) 2d-(20) 2d-(20) 2d-(21)2f-(21) 2e-(20) 2g-(23) 2e-(22) 2g-(22)2i-(22) 2f-(22) 2i-(20) 2g-(21) 2j-(23)2j-(24) 2h-(23) 2j-(21) 2j-(22)2i-(22)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 2356

STUDIES ON SULPHONAMIDESStudies on SulphonamidesINTRODUCTIONThe discovery of sulphonamides as drugs is considered to be the beginning ofchemotherapeutic era by making possible a direct attack on microbial infection.Sulphonamide was first prepared by Glemo in 1908. Gerhald Domagk in 1935tested prontosil towards infection by hemolytic streptococci and found it veryeffective antibacterial which lead to the synthesis of newer molecules byincorporating different nucleus. Sulphonamides have the general structure R-SO 2 - N-R′, R″, where R=organic radical, R′,R″=hydrogen or organic radical. They areclassified as aliphatic, aromatic and heterocyclic which is depending upon the natureof R. Aromatic and heterocyclic sulphonamides have achieved greater commercialsignificance. Their application on chemotherapy is so well known that the name,‘sulpha drug’ is widely used as a general name for sulphonamide derivatives astherapeutic agent.THERAPEUTIC IMPORTANCE AND SYNTHETIC ASPECTIt has been now well established that sulphonamides possess valuablebiological properties including,1. Hypoglycemic 1602. Antimalarial 1613. Antiinflammatory 1624. Herbicidal 1635. Anticoagulant 1646. Anti-HIV 1657. Antitumer 1668. Antihypertension and antiglaucoma 1679. Antimicrobial 16810. Antidiabetic 16911. Anticancer and antibacterial 17012. Herbicidal 17113. Potassium channel inhibitor 17214. Antibacterial 173 57

Studies on SulphonamidesSulphonamides showed good biological activities. Due to these many sulphonamide derivatives are recently in clinical use some of them are shown below.C H 3OH CNH3 N2NSO 2NHMethazolamide(CA inhibitor)NO 2H 5 C 2ONSEthoxzolamide(CA inhibitor)OSO 2NH 2FONS-398 NH(COX-inhibitor)SO 2 CH 3FOFlosulide(COX-inhibitor)NH SO 2 CH 3NH 2NH 2SO 2 -NH 2SO 2 -NH 2ClChlorphenaide(diuretic)SO 2 -NH 2Sulphanilamide(antibacterial)SO 2 -C 6 H 4 -NH 2Dapsone(antileprotic)H 3 CONSO 2 NH CO NHH 3 CONHNSO 2 NH 2Sulphodoxine(antimalarial)ClNH 3 C CH 3Glyparamide(antidiabetic)Sulphonamides continue to be used as antibacterial as they are effective,inexpensive and free of super infection of problems caused by antibiotics. Extensiveresearch has been carried out to enhance the activity and reduced toxicity of sulphadrugs.58

Studies on SulphonamidesRecently two isoenzymes of cyclooxy genase have been identified: COX-1and COX-2 selective inhibition of COX-2 or dual inhibition of COX-1 and COX-2 isunder discussion as a promising principle in the treatment of inflammatory diseases.For several reasons, including increased cardiovascular risk, the important role ofCOX-2 produced prostaglandins in the response of the mucosa to irritants and inhealing and other critical aspects the accuracy of selective COX-2 inhibition as theprinciple tent is under debate.A number of substituted sulphonamides are known as antiinflammatory agent.The substances were diflumidone and nimesulide which was lead NS-348 andflosulide.Diarylmethanoes such as ketoprofen, tiaprofenic acid, tolmetine and ketorolacare used in the therapy of inflammation.The objective of this study was to correlate the structural parameters with theinhibitory potency and the enzyme selectivity i.e. to evaluate the significance ofsulphonamides as latest biologically active compounds.Moreover G. Dannhardt et.al 174 have described the synthesis and COX-1/COX-2 inhibitory activity of some sulphonamides.C H 3OHNSO 2HNSO 2CH 3Cox-1 and Cox-2 inhibitorsCH 3C. T. Supuran et. al. 175 have documented some CA inhibitors. CA isconcerning to von-Hippel-Lindau tumors. Progressive polycystic kidney disease,carcinomas of the pancreas of Autoimmune/idiopathic chronic pancreatities, itappeared of great interest to further explore the connections between CAs and tumors.59

Studies on SulphonamidesFXFSO 2 NH OCH 3FFCarbonic Anhydrase (CA) isozyme inhibitorsP. P. Stein et.al. 176 have reported arylsulphonaidopiperidones and also testedbiological activity such as inhibitors of Factor Xa.D. Dushyant et.al. 177 synthesized some sulphonamides as antagonist ofurotensin- II.H 3 COH 3 COSO 2NHOO CH 3Antagonist of urotensin-IIClNCH 3CONTRIBUTION FROM OUR LABORATORYA. R. Parikh and Co-workers 178 (I) have evaluated several sulphonamidederivatives having the general formula R-SO 2 -NH-R′, where R= phenyl, substitutedphenyl, α and β-napthyl and R′= 2, 4-distributed s-triazine. 179V. H. Shah and Coworkers 180-185 (II) have synthesized new sulphonamidederivatives and evaluated its antimicrobial screening.D. M. Purohit et. al. 186 (III) have synthesized new piperazine sulphonamidederivatives and evaluated its antimicrobial activity.60

Studies on SulphonamidesCH 3CH 3ORF 3 CRNHSO 2 N NN NNHCOCH2 NHR'NH N SO 2 -PhPhSO 2 N SO 2 -PhN CH 3( I ) ( I ) ( II )NO 2CH 2 CH 2 NHNHSO 2 RNO 2 NCH 2 CH 2 CH 3NO 2( II ) ( II )NO 2NO 2NHSO 2 RRSO 2 NHNHSO 2NOCH 2 COOHClCl( II )OClSO 2 R RONNN NSO 2R'Ph( II ) ( II )ClOCH 2 COOHClN( III )N NHOSROR=R'= ArylB. R. John et. al. 187 has prepared some sulphonamide derivatives as potentantidiabetic agent. More recently A. R. Mishra et. al. 188 and O. A. Fathalla 189 havereported some novel sulphonamides as antifungal, pesticidal and anticancer agent.With a view to get better therapeutic agent, it was contemplated to synthesizesulphonamide derivatives to enhance the overall activity of resulting compoundswhich have been described as under.SECTION-I: SYNTHESIS AND BIOLOGICAL SCREENING OF 1-ARYLSULPHO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.SECTION-II: SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLSULPHONAMIDO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.61

Studies on SulphonamidesSECTION – ISYNTHESIS AND BIOLOGICAL SCREENING OF 1 - ARYLSULPHO - 4 -[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.With an aim to getting better therapeutic agent of sulphonamidesderivatives and considering the association of various biological activity suchas antibacterial, antifungal, anticonvulsant, antimalarial, tuberculosis,antiviral etc. of piperazine nuclei, the synthesis of 1 - arylsulpho - 4 - [(4', 4"-difluorodiphenyl) - methyl] - piperazines of Type (III) have been undertaken bythe condensation of 1 - (H)- 4 - [(4',4" -difluorodiphenyl)-methyl]-Piperazine witharylsulphonyl chloride in presence of pyridine.FNNHNOSROFType-IIIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no-A.62

Studies on SulphonamidesIR SPECTRAL STUDY OF 1-[(4"'-METHYLPHENYL)-SULPHO]-4-[(4', 4"-DIFLUORODIPHENYL)-METHYL]- PIPERAZINE.FON N SCH 3OFInstrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).TypeAlkaneAromaticVibration Frequency in cm -1Ref.mode Observed ReportedC-H str.(asym.) 2989 2990-2850 474C-H str. (sym.) 2891 2880-2860 "C-H def.(asym.) 1444 1470-1435 "C-H def. (sym.) 1375 1390-1370 "C-H str. 3091 3090-3030 "C=C str 1502 1600-1450 "C-H i.p. (def.) 1172 1300-1100 "Halide C-F str. 732 800-600 475Piperazine C-N str. 1329 1360-1310 "S=O str. (asym.) 1329 1380-1300 "Sulphonamide S=O str. (sym.) 1126 1180-1140 "C-S str. 732 750-600 "63

Studies on SulphonamidesNMR SPECTRAL STUDY OF 1 - [(4"'- METHYLPHENYL) - SULPHO] - 4 -[(4',4" -DIFLUORODIPHENYL)-METHYL]- PIPERAZINE.Fgg'hh'edOcbifN N Se' d' Oc'b'CH 3aji'j'FInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference12.36-2.38 4H doublet C-H (ee’)2.413Hsinglet Ar-CH 3 (a)2 2.53-2.91 4H doublet C- H (dd’)3 6.18 1H singlet C-H (f)4 8.88-8.91 4H doublet Ar-H (gg’, jj’)5 9.22-9.40 6H ddoublet Ar-H (hh’, ii’, bb’)7 9.55-9.57 2H doublet Ar-H (cc')64

Studies on SulphonamidesMASS SPECTRAL STUDY OF 1-[(4"'-METHYLPHENYL)-SULPHO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.65

MASS FRAGEMENT STUDY OF 1 - [(4"' - METHYLPHENYL) - SULPHO] - 4 - [(4', 4"- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE.Studies on SulphonamidesFCH 3+oFm/z = 96+oCH 3m/z = 92+oH NNm/z = 288+Oo+S NNoOFC H 3m/z = 348FF+oOOSNH 2m/z = 171ON H 2m/z = 219FFFNNSOCH 3F+om/z = 442H 3 C NH 3 Cm/z = 275F+oFOS +ONNm/z = 351FH Nm/z = 86NH+oC H 3OOS Nm/z = 240NH+oFm/z = 204F+oC H 3C H 3OSNOm/z = 227CH 3+o66

REACTION SCHEMEStudies on SulphonamidesFFOHTolueneSOCl 2RefluxFFClPiperazineTolueneRefluxFNNHFOPyridineRSClFOON N SROFType - IIIR = Aryl67

Studies on SulphonamidesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1 - ARYLSULPHO - 4 -[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.[A] Synthesis of 1-chloro-1-[(4',4"-difluorodiphenyl)-methane:See, Part-I, Section-I (A), on page no-39[B] Synthesis of 1 -[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-I (B), on page no-39[C] Synthesis of 1-[(4"'-methylphenyl)-sulpho]- 4 -[(4',4"-difluorodiphenyl)-methyl]- piperazine(3j):A mixture of 1-(H)-[(4',4"-difluorodiphenyl)-methyl]-piperazine (2.88gm.0.01M), 4-methylbenzenesulphonyl chloride (1.90g, 0.01M),pyridine(10 ml) washeated in a oil bath at 120°C for 5-6 hours. The reaction mixture was cooled andpoured into crushed ice, neutralized with diluted hydrochloric acid. The product isfiltered, washed with water and crystallized from isopropyl alcohol. M.P. 189°C,yield: 75%.(C 24 H 24 O 2 N 2 F 2 S: Required: C:65.15; H:5.42; N:6.33; Found: C:65.10; H:5.41;N:6.30 %).Similarly, other sulphonamides were synthesized. The physical data arerecorded in Table no -3.[D] Biological Screening of 1-arylsulpho-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.Biological screening were carried out as described in Part-I, Section-I, pageno-40. The zones of inhibition of test solutions are recorded in Graphical Chart no-3.68

Studies on SulphonamidesTABLE NO- 3: PHYSICAL COSTANTS OF 1 - ARYLSULPHO - 4 -[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.3a 3-COOH-C 6 H 4 - C 24 H 22 O 4 N 2 F 2 S 472 150 71.10 5.93 5.903b 5-COOH-2-CH 3 -C 6 H 3 - C 25 H 24 O 4 N 2 F 2 S 486 202 66.71 5.76 5.713c 3-COOH-4-CH 3 -C 6 H 3 - C 25 H 24 O 4 N 2 F 2 S 486 123 61.62 5.76 5.703d 5-COOH-2-OCH 3 -C 6 H 3 - C 25 H 24 O 5 N 2 F 2 S 502 200 79.81 5.57 5.523e 3-COOH-4-OCH 3 -C 6 H 3 - C 25 H 24 O 5 N 2 F 2 S 502 227 65.50 5.57 5.503f 5-COOH-2-Cl-C 6 H 3 - C 24 H 21 O 4 N 2 F 2 ClS 506 120 66.60 5.53 5.473g 3-COOH-4-NO 2 -C 6 H 3 - C 24 H 21 O 6 N 3 F 2 S 517 159 76.52 8.12 8.003h 3-COOH-5-NO 2 -C 6 H 3 - C 24 H 21 O 6 N 3 F 2 S 517 180 62.76 8.12 8.083i 5-COOH-2-NO 2 -C 6 H 3 - C 24 H 21 O 6 N 2 F 2 S 517 197 74.40 8.12 8.043j 4-CH 3 -C 6 H 4 - C 24 H 24 O 2 N 2 F 2 S 442 189 75.00 6.33 6.3069

Studies on SulphonamidesGRAPHICAL CHART NO- 3 : BIOLOGICAL SCREENING OF 1 - ARYLSULPHO - 4 -[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.30ZONE OF INHIBITION IN mm25201510503a 3b 3c 3d 3e 3f 3g 3h 3i 3j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 17 22 19 21 23 18 24 16 21 22 23 22 24 0B.cerus 18 22 19 21 17 23 16 20 15 19 22 23 21 0E .coli 20 16 21 19 17 22 16 19 18 23 21 21 23 0E .aerogen 18 20 19 21 16 15 19 22 17 16 19 20 22 0A.niger 21 22 19 21 18 16 23 18 19 22 0 0 0 2370

Studies on SulphonamidesPART-IISECTION – I: BIOLOGICAL SCREENING STUDY OF 1 - ARYLSULPHO - 4 - [(4', 4"- DIFLUORODIPHENYL) - METHYL] -PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger3b-(22) 3b-(22) 3a-(20) 3a-(18)3a-(21)3d-(21) 3d-(21) 3c-(21) 3b-(20) 3b-(22)3e-(23) 3f-(23) 3f-(21) 3c-(19) 3d-(21)3g-(24) 3h-(20) 3j-(23) 3d-(21) 3g-(23)3i(21) 3g-(19) 3j-(22)3j-(22)3h-(22)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 2371

Studies on SulphonamidesSECTION-IISYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLSULPHONAMIDO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sulphonamides derivatives shows better therapeutic activity such asantiviral, anti-inflammatory, antibacterial, antifungal, antimalarial etc. ofpiperazine nuclei. In view of getting to synthesis 1-N-arylsulphonamido-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines of Type (IV) have been undertakenby the condensation of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-Piperazine witharylsulphonyl chloride in presence of pyridine.FNNNHOSORFType-IVR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no- A.72

Studies on SulphonamidesIR SPECTRAL STUDY OF 1 - N - [(4"' - METHYLPHENYL) - SULPHONAMIDO] - 4 - [(4', 4"- DIFLUORODIPHENYL) - METHYL] - PIPERAZINE.FNNHSONOCH 3FInstrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration Frequency in cm -1 Ref.Mode Observed ReportedC-H str.(asym.) 2923 2990-2850 474AlkaneC-H str. (sym.) 2873 2880-2860 "C-H def. (asym.) 1402 1470-1435 "C-H def. (sym.) 1373 1390-1370 "C-H str. 3031 3090-3030 "Aromatic C=C str 1573 1600-1450 "C-H i.p. (def.) 1170 1300-1100 "Halide C-F str. 808 800-600 475Piperazine C-N str. 1326 1360-1310 "C-S str. 703 750-600 "Sulphonamide S=O str. (asym.) 1326 1300-1380 "S=O str. (sym.) 1151 1180-1140 "Sec. amide N-H str. 3240 3500-3100 "73

Studies on SulphonamidesNMR SPECTRAL STUDY OF 1 - N - [(4"'- METHYLPHENYL) - SULPHONAMIDO] - 4 - [(4',4"- DIFLUORODIPHENYL) - METHYL] - PIPERAZINE.Fh'hi'jigfNj'ef'd ONHN SOe'c'cb'bCH 3akk'FInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.35-2.404Hdoublet C-H (ff’)3Hsinglet Ar-CH 3 (a)2 2.53-2.59 4H doublet C-H (ee’)3 5.20 1H singlet C-H (g)4 6.93-7.02 4H triplet Ar-H (hh’, kk’)5 7.12-7.19 4H triplet Ar-H (ii’, jj’)6 7.37-7.43 2H doublet Ar-H (bb’')7 7.76 1H singlet N-H (d)8 7.99-8.01 2H doublet Ar-H (cc')74

Studies on SulphonamidesMASS SPECTRAL STUDY OF 1-N-[(4"'-METHYLPHENYL)-SULPHONAMIDO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.75

Studies on SulphonamidesMASS FRAGEMENT STUDY OF 1-N-[(4"'-METHYLPHENYL)-SULPHONAMIDO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.F+oF+oCH 3CH 3F+oCH 3+oH NNm/z = 288FN H 2NNm/z = 303FOOS NNHm/z = 255NH+oOSONNHm/z = 363NF+oOSONH 2FN H 2m/z = 171m/z = 219FFCH 3F+oCH 3NH 3C+oFOSONHNNm/z = 457FOS +ONHNNFm/z = 275CH 3m/z = 366FFCH 3+om/z = 96+oCH 3OSO NHm/z = 186+oNH 2m/z = 92CH 3+oHNNHm/z = 86+om/z = 204+oFOSONNHm/z = 242CH 376

Studies on SulphonamidesREACTION SCHEMEFNNHFFNaNO 2 + HCl0-5 0 CN N NOFFLiAlH 4N N NH 2OFFR S ClOPyridineN N NHSOORType - IVFR = Aryl77

Studies on SulphonamidesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLSULPHONAMIDO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.[A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1 - N - [(4"'- methylphenyl)-sulphonamido] - 4 - [(4',4" -difluorodiphenyl)-methyl]-piperazine(4j):A mixture of 1- amino - 4 - [(4',4"-difluorodiphenyl)-methyl] - piperazine(3.03gm, 0.01M), 4-methylbenzenesulphonyl chloride(1.90g, 0.01M), pyridine(20 ml)was heated in a oil bath at 120°C for 8 hours. The reaction mixture was cooled andpoured into crushed ice, neutralized with diluted hydrochloric acid. The product isfiltered, washed with water and crystallized from isopropyl alcohol. M.P. 172°C,yield: 72.00 %. (C 24 H 25 O 2 N 3 F 2 S; Required: C:63.00; H:5.51; N:9.18; Found: C:62.97;H:5.49; N:9.15 %).Similarly, other sulphonamides were synthesized. The physical data arerecorded in Table no - 4.[D] Biological screening of 1 - N - arylsulphonamido - 4 - [(4',4"-difluorodiphenyl)-methyl]-piperazines.Biological screening were carried out as described in Part-I, Section-I, pageno-40. The zones of inhibition of test solutions are recorded in Graphical Chart no- 4.78

Studies on SulphonamidesTABLE NO - 4: PHYSICAL CONSTANTS OF 1-N-ARYLSULPHONAMIDO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.4a 3-COOH-C 6 H 4 - C 24 H 23 O 4 N 3 F 2 S 487 171 73.14 8.62 8.614b 5-COOH-2-CH 3 -C 6 H 3 - C 25 H 25 O 4 N 3 F 2 S 501 194 67.74 8.38 8.364c 3-COOH-4-CH 3 -C 6 H 3 - C 25 H 25 O 4 N 3 F 2 S 501 154 66.52 8.38 8.364d 5-COOH-2-OCH 3 -C 6 H 3 - C 25 H 25 O 5 N 3 F 2 S 517 217 75.41 8.12 8.094e 3-COOH-4-OCH 3 -C 6 H 3 - C 25 H 25 O 5 N 3 F 2 S 517 202 67.56 8.12 8.094f 5-COOH-2-Cl-C 6 H 3 - C 24 H 22 O 4 N 3 F 2 ClS 521 168 63.69 8.05 8.034g 3-COOH-4-NO 2 -C 6 H 3 - C 24 H 22 O 6 N 4 F 2 S 532 178 77.54 10.52 10.504h 3-COOH-5-NO 2 -C 6 H 3 - C 24 H 22 O 6 N 4 F 2 S 532 194 64.70 10.52 10.504i 5-COOH-2-NO 2 -C 6 H 3 - C 24 H 22 O 6 N 4 F 2 S 532 209 78.45 10.52 10.504j 4-CH 3 -C 6 H 4 - C 24 H 25 O 2 N 3 F 2 S 457 172 72.00 9.18 9.1579

Studies on SulphonamidesGRAPHICAL CHART NO- 4 : BIOLOGICAL SCREENING OF 1 - N - ARYLSULPHONAMIDO - 4 - [(4',4"- DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.30ZONE OF INHIBITION IN mm25201510504a 4b 4c 4d 4e 4f 4g 4h 4i 4j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 20 18 17 19 21 20 17 22 24 22 23 22 24 0B.cerus 18 21 19 22 23 17 20 19 16 21 22 23 21 0E .coli 20 15 19 16 22 20 18 17 23 20 21 21 23 0E .aerogen 18 20 17 19 16 17 20 16 22 21 19 20 22 0A.niger 18 22 16 18 21 19 23 17 18 22 0 0 0 2380

PART-IIStudies on SulphonamidesSECTION–II: BIOLOGICAL SCREENING STUDY OF 1-N-ARYLSULPHONAMIDO-4-[(4',4"-DIFLUORODIPHENYL) -METHYL]-PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger4e-(21) 4b-(21) 4a-(20) 4a-(18) 4b-(22)4h-(22) 4d-(22) 4e-(22) 4b-(20) 4e-(21)4i-(24) 4e-(23) 4f-(20) 4d-(19) 4g-(23)4j-(22) 4g-(20) 4i-(23) 4g-(20) 4j-(22)4j-21) 4j-(20) 4i-(22)4j-(21)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 2381

STUDIES ON MANNICH BASESStudies on Mannich BasesINTRODUCTIONMannich reaction consists of the condensation of ammonia orprimary/secondary amine, usually as the hydrochloride, with formaldehyde or otheraldehyde, and a compound containing atleast one hydrogen atom of pronouncedreactivity.In 1912, Carl Mannich has investigated this reaction. Today, due to itswide range of biological activities, much interest has been focused on this reaction.Mostly, they are found to be antineoplastic, analgesic and antibiotic agents.Mannich bases are also employed as an intermediate in industrial chemicalsynthesis.Mannich 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. 190-192 Mannich base derivatives with bridge N-atom have beenfound to be potent drug in medicinal science and possess wide range of biologicalactivities like antibacterial, antimalarial, analgesic, anti-inflammatory, anticonvulsant,anthelmintics, etc. Mannich bases have gained important because of theirtechnological applications in polymer chemistry 193 , especially as paints and surface.active agents and exhibits complexation characteristic with many transition metalions. Over the years there has been much contraversy about the mechanism of theMannich reaction. Studies of the reaction kinetics have led to the followingmechanistic proposals.82

Studies on Mannich BasesSYNTHETIC ASPECTDifferent methods have cited in literature to synthesize Mannich bases byseveral workers 194,195 using various interesting substractes.1. P. G. Venkatesha and D. Vanappayya 196 have synthesized aminobenzylatedMannich bases by the condensation reaction between heterocyclic secondaryamines and benzaldehyde.2. Seshaiah Krishnan et. al. 197 have synthesized Mannich bases from the schiffbases of isatin in presence of formaldehyde and diphenyl amine.RRNNNNHHRR 1 1HCHO RHCHO ROO CC 6 H6 H 5 5HNHNCC 6 H6 H 5 5R=H,Cl,BrR=H,Cl,BrRR 1 =-C1 =-C 6 H6 H 4 Br,-C4 Br,-C 6 H6 H 4 CH4 CH 3 3RR 2 =-N(C2 =-N(C 6 H6 H 5 ) 2 5 ) 2NNNNRR 1 1OORR 2 283

Studies on Mannich Bases3. Yung-son Hon et. al. 198 have prepared Mannich base from the reaction ofphenolic compounds with a preheated mixture of dibromomethane anddiethylamine.CH 3CH 3NOH[CH[CH 2 Br Br 2 ,NH(Et) ,NH(Et) 2 ]OH4. S. N. Pandeya and D. Sriram Dave 199 have synthesized Mannich basesby the condensation of the acidic group of isatin with formaldehyde andsecondary amines.5. K. W. Chi and co-workers 200 have synthesized Mannich base using1,4,10,13-tetraoxa-7,16 diazacyclooctadecane, formaldehyde and phenolicderivatives in benzene.6. A. Christos Kontogiorgis et. al. 201 have synthesized Mannich base ofcoumarine.THERAPEUTIC IMPORTANCEMannich bases are associated with a wide variety of biological activities andtherapeutic applications such as,1. Anti-inflammatory 202-2042. Antifungal 2053. Antitumor 2064. Analgesic 2075. Cytotoxic and anticancer 2086. Antibacterial 2097. Antipsychotic 2108. Tranquilizer 211,2129. Antileishmanial 21310. Antimalarial 214 84

Studies on Mannich BasesT. Lorand and B Kocsis 215 have synthesized some new Mannich bases andreported their antibacterial activity. D. D. Erol, A. Rosen et. al. 216 have synthesizedsome new Mannich base derivatives from 6-acyl-3-(3,5-dimethylpiperidinomethyl)-2(3H)-benzoxazolones and reported their biological activities. H. M. Hassan et. al. 217have synthesized some new Mannich bases containing 1,8-napthyridine moiety andreported their antimicrobial activity.M. Movrin and D. Maysinger 218 have synthesized Mannich bases fromnitroxoline and reported them as biologically active agents. T. Ojanen andcoworkers 219 have reported antifungal activity of some mono, bis and quaternaryMannich bases derived from acetophenone. Y. Li, Z. S. Yang et. al. 220 havesynthesized some Mannich base derivatives and reported their antimalarial activity.B. Shivarama Holla et. al. 221 have prepared Mannich bases and tested themfor anthelmintic activity (I) and all the newly synthesized compounds (II) were testedfor their antibacterial and antifungal activity.N N CH 3NONNNNRNSO 2 NRNSO 2 NNO OCH 3NO OCH 3( I ) ( II )Amodiaquine, 222,223 Mannich base derivatives (III) which shown anantimalarial activity superior than chloroquine in areas of high chloroquine resistance.M. L. Edwards et. al. 224 have prepared the Mannich base of 4-phenyl-3-buten-2-one asan antiherps agent. K. Malcolm Scott and co-workers 225 have prepared the pyrrolemannich base (IV) as a potent antipsychotic agent.85

Studies on Mannich BasesCH 3CH 3NCH 3CH 3R 1HON3 NRNRR 2 NN(CH 2 )nHONHClN( III ) ( IV )J. Knoll et. al. 226 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. 227 Jan Balzarini andco-workers 228 have prepared the Mannich bases of chalcone shows cytotoxicactivities.H 3 CCONH 3 CCHNNOH 3( V ) ( VI )H 3OH. I. Gul et. al. 229,230 have documented antifungal activity of bis Mannichbases derived from acetophenones and some mono Mannich bases evaluated for theiranticonvulsant activity. M. S. Shingare et. al. 231 have described the synthesis and theantiviral activity of Mannich bases (VII).86

Studies on Mannich BasesNNSRNSNRNHSR= H, 4-Me, 5-OMe, 5-Cl, 6-Br( VII )S. vijayraghavan et al. 232 have prepared 5-[2-(ethylthio)-1H-benzimidazol-1-yl]-methyl-3-[(arylamino)-methyl]-1,3,4-oxadiazole-2-thiones (Mannich bases) andtested them for antibacterial activity (VIII).NSCH 2 CH 3NNNCH 2 NR 1 R 2SR 1 =HOR 2 =Phenyl, Substituted phenyl etc.( VIII )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 sections.SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 1 -ARYLAMINOMETHYL-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING OF 1 - N -(ARYLAMINOMETHYLAMINO) - 4 - [(4',4"- DIFLUORODIPHENYL) - METHYL] -PIPERAZINES.87

Studies on Mannich BasesSECTION-ISYNTHESIS AND BIOLOGICAL SCREENING OF 1 - ARYLAMINOMETHYL -4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.Mannich bases reported in literature exhibit biodynamic activities like antiinflammatory,antifungal, antibacterial, analgesic, anticonvulsant etc., with a view ofgetting to synthesis 1 - arylaminomethyl - 4 - [(4',4"- difluorodiphenyl) - methyl] -piperazines of Type (V) have been synthesized from 1-(H)-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine with aryl amine, formaldehyde in presence ofhydrochloric acid in methanol.FNNNH RFType-VR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.88

Studies on Mannich BasesIR SPECTRAL STUDY OF 1-[(4"'-METHOXYPHENYL)-AMINOMETHYL]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.FNNCH 3NHOFInstrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration Frequency in cm -1 Ref.mode Observed ReportedC-H str.(asym.) 2958 2990-2850 474AlkaneC-H str. (sym.) 2877 2880-2860 "C-H def. (asym.) 1467 1470-1435 "C-H def. (sym.) 1388 1390-1370 "Alkene -CH 2 str. 2793 2850-1790 "C-H str. 3047 3090-3030 475Aromatic C=C str 1500 1600-1450 "C-H i.p. (def.) 1282 1300-1100 "Halide C-F str. 786 800-600 "Piperazine C-N str. 1352 1360-1310 "Ether C-O-C str. 1232 1280-1200 "Mannich base C-N str. 1041 1220-1020 "Sec. amine N-H str. 3310 3500-3100 "89

Studies on Mannich BasesNMR SPECTRAL STUDY OF 1 - [(4"' - METHOXYPHENYL) - AMINOMETHYL]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.Fh'hkiji'gj'NffffNedNHcc'bb'OCH a3Fk'Internal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.23-2.37 8H doublet C-H (f)2 2.72-2.74 1H singlet N-H (d)3 3.82 3H singlet Ar-OCH 3 (a)4 4.11 2H singlet C-H (e)5 5.22-5.23 1H singlet C-H (g)6 6.86-6.89 6H doublet Ar-H (cc’,hh’,kk’)7 7.24-7.27 6H doublet Ar-H (bb’, ii’, jj’)90

Studies on Mannich BasesMASS SPECTRAL STUDY OF 1-[(4"'-METHOXYPHENYL)-AMINOMETHYL]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.91

Studies on Mannich BasesMASS FRAGEMENT STUDY OF 1-[(4"'-METHOXYPHENYL)-AMINOMETHYL]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.F+oF+oOCH 3OCH 3F+oOCH 3+oH NNm/z = 288FC H 3NNm/z = 302FH NNm/z = 221NH+oH NNm/z = 329NF+oH NCH 3m/z = 137FOCH 3FN H 2m/z = 219FFN+oCH 3NH 3+oH NNm/z = 423FNCm/z = 275FFN H 2NOm/z = 317Fm/z = 96+oCH 3OCH 3OH+o +N+ooNm/z = 108HH N NH 2m/z = 86m/z = 152CH 3O+oNH 2m/z = 123Fm/z = 204CH 3OH NCH 3N+H N N+ooF m/z = 235CH 3CH 3NCH 3m/z = 208+o92

Studies on Mannich BasesREACTION SCHEMEFFOHTolueneSOCl 2RefluxFFClPiperazineTolueneRefluxFNNHFFHCHOR-NH 2NNNH RFType - VR = Aryl93

Studies on Mannich BasesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1 - ARYLAMINOMETHYL-4-[(4',4"-DIFLUORODIPHENYL)-METHYL] -PIPERAZINES.[A] Synthesis of 1-chloro-1-[(4',4"-difluorodiphenyl)-methane:See, Part-I, Section-I (A), on page no-39[B] Synthesis of 1 -[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-I (B), on page no-39[C] Synthesis of 1 - [(4"'-methoxyphenyl)-aminomethyl] - 4 - [(4',4"-difluorodiphenyl)-methyl]-piperazine(5f):A mixture of 1-(H)-[(4',4"-difluorodiphenyl)-methyl]-piperazine.(2.88gm,0.01M), 4-methoxyaniline (1.23gm, 0.01M), formaldehyde (1ml), concentratedhydrochloric acid(0.5 ml) and methanol(25 ml) was refluxed for 6 hrs. The contentswere cooled and poured into crushed ice, neutralized with 10% NaHSO 3 solution. Theisolated product was filtered washed with water. The product was crystallized fromethanol. M.P. 210°C, yield: 88.10%. (C 25 H 27 ON 3 F 2 : Required: C:70.92; H:6.38;N:9.92; Found: C: 70.88; H:6.30; N:9.85%).Similarly, other Mannich bases were synthesized. The physical data arerecorded in Table no -5.[E] Biological screening of 1 - arylaminomethyl-4-[(4',4"-difluorodiphenyl)-methyl] -piperazines:Biological screening were carried out as described in Part-I, Section-I, pageno-40. The zones of inhibition of test solutions are recorded in Graphical Chart no-5.94

Studies on Mannich BasesTABLE NO - 5 : PHYSICAL CONSTANTS OF 1 - ARYLAMINOMETHYL - 4 - [(4', 4"- DIFLUORODIPHENYL) - METHYL] -PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.5a C 6 H 5 - C 24 H 25 N 3 F 2 393 158 70.91 10.68 10.655b 2-CH 3 -C 6 H 4 - C 25 H 27 N 3 F 2 407 170 78.19 10.31 10.255c 3-CH 3 -C 6 H 4 - C 25 H 27 N 3 F 2 407 179 75.16 10.31 10.285d 4-CH 3 -C 6 H 4 - C 25 H 27 N 3 F 2 407 180 58.81 10.31 10.325e 2-OCH 3 -C 6 H 4 - C 25 H 27 ON 3 F 2 423 154 68.11 9.92 9.895f 4-OCH 3 -C 6 H 4 - C 25 H 27 ON 3 F 2 423 210 88.10 9.92 9.855g 2-Cl-C 6 H 4 - C 24 H 24 N 3 F 2 Cl 427 176 72.82 9.82 9.795h 2-NO 2 -C 6 H 4 - C 24 H 24 O 2 N 4 F 2 438 157 65.41 12.78 12.705i 3-NO 2 -C 6 H 4 - C 24 H 24 O 2 N 4 F 2 438 130 89.16 12.78 12.755j 4-NO 2 -C 6 H 4 - C 24 H 24 O 2 N 4 F 2 438 163 74.02 12.78 12.7295

Studies on Mannich BasesGRAPHICAL CHART NO- 5 : BIOLOGICAL SCREENING OF 1 - ARYLAMINOMETHYL - 4 - [(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.30ZONE OF INHIBITION IN mm25201510505a 5b 5c 5d 5e 5f 5g 5h 5i 5j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 18 21 20 19 18 24 19 23 18 22 23 22 24 0B.cerus 22 20 16 19 21 19 15 22 18 23 22 23 21 0E .coli 19 21 20 17 23 18 21 20 18 16 21 21 23 0E .aerogen 18 16 20 17 20 21 14 17 19 22 19 20 22 0A.niger 22 18 21 16 19 22 20 23 17 21 0 0 0 2396

Studies on Mannich BasesPART-IIISECTION - I : BIOLOGICAL SCREENING STUDY OF 1-ARYLAMINOMETHYL-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger5b-(21) 5a-(22) 5b-(21) 5a-(18)5a-(22)5c-(20) 5b-(20) 5c-(20) 5c-(20) 5c-(21)5f-(24) 5e-(21) 5e-(23) 5e-(20) 5f-(22)5h-(23) 5h-(22) 5g-(21) 5f-(21) 5h-(23)5j-(22) 5j-(23) 5h-(20) 5i-(19) 5j-(21)5j-(22)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 2397

Studies on Mannich BasesSECTION-IISYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-(ARYLAMINOMETHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Mannich bases showed pharmacological activities like anthelmintics,antibacterial, antifungal, antimalarial, anticonvulsant, analgesics etc. In view ofgetting better therapeutic activity to synthesis 1 - N - (arylaminomethylamino) - 4 -[(4', 4"- difluorodiphenyl) - methyl] - piperazines of Type (VI) have been synthesizedfrom 1 - amino - 4 - [(4',4" - difluorodiphenyl) - methyl] - piperazine with aryl amine,formaldehyde in presence of hydrochloric acid in methanol.FNNNHRNHFType-VIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.98

Studies on Mannich BasesIR SPECTRAL STUDY OF 1-N-[(4"'-METHOXYPHENYL)-AMINOMETHYLAMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.FNHNHNNOCH 3FInstrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration Frequency in cm -1 Ref.mode Observed ReportedC-H str.(asym.) 2958 2990-2850 474AlkaneC-H str. (sym.) 2865 2880-2860 "C-H def. (asym.) 1452 1470-1435 "C-H def. (sym.) 1371 1390-1370 "Alkene -CH 2 str. 2367 2850-1790 "C-H str. 3047 3090-3030 475Aromatic C=C str 1512 1600-1450 "C-H i.p. (def.) 1280 1300-1100 "Halide C-F str. 773 800-600 "Piperazine C-N str. 1359 1360-1310 "Ether C-O-C str. 1255 1280-1200 "Mannich base C-N str. 1172 1220-1020 "Sec. amine N-H str. 3409 3500-3100 "Amine N-H str. 3367 3500-3100 "99

Studies on Mannich BasesNMR SPECTRAL STUDY OF 1-N-[(4"'-METHOXYPHENYL)-AMINOMETHYLAMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.Fjj'kk'ihNgh'fNHNeg'dNHcc'bb'OaCH 3lml'm'FInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.19-2.39 4H doublet C-H (hh’)2 2.56-2.72 4H doublet C-H (gg’)3 3.78 3H singlet Ar-OCH 3 (a)4 4.0 2H singlet C-H (e)5 6.13 1H singlet C-H (i)6 6.95-6.99 4H doublet Ar-H (jj’, mm’)7 7.10-7.12 1H singlet N-H (f)8 7.21-7.29 2H doublet Ar-H (bb’)9 7.35-7.46 4H doublet Ar-H (kk’, ll’)10 7.60-7.632H1HdoubletsingletAr-H (cc’)N-H (d)100

Studies on Mannich BasesMASS SPECTRAL STUDY OF 1-N-[(4"'-METHOXYPHENYL)-AMINOMETHYLAMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.101

Studies on Mannich BasesMASS FRAGEMENT STUDY OF 1-N-[(4"'-METHOXYPHENYL)-AMINOMETHYLAMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.F+oF+oOCH 3OCH 3F+oOCH 3+oH NNm/z = 288FN H 2NNm/z = 303FH NNNHm/z = 236NH+oH NNNHm/z = 344NF+oH NCH 3m/z = 137FN H 2m/z = 219FFOCH 3FN+oCH 3NH 3+oH NNHNm/z = 438FNCm/z = 275OCH 3FC H 3NHNOCH 3m/z = 317Fm/z = 108+oCH 3O+oH N NH 2m/z = 152OCH 3NH 2m/z = 123+oHNNHm/z = 86+oFm/z = 204F+oFm/z = 96H 2 N+oNHNNFm/z = 332NH N NHm/z = 223F+o+oCH 3CH 3102

Studies on Mannich BasesREACTION SCHEMEFNNHFFNaNO 20-5 0 C+ HClN N NOFFLiAlH 4N N NH 2FFHCHOR-NH 2N N NHRNHType - VIFR = Aryl103

Studies on Mannich BasesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-(ARYLAMINOMETHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.[A]Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B]Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4"'-methoxyphenyl)-aminomethylamino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine(6f):A mixture of 1- amino- 4 -[(4',4"-difluorodiphenyl) - methyl] - piperazine(3.03gm, 0.01M),4-methoxyaniline(1.23gm,0.01M),formaldehyde(2 ml), concentratedhydrochloric acid(0.5 ml) and methanol(25 ml) was refluxed for 6 hrs. The contentswere cooled and poured into crushed ice, neutralized with 10% NaHSO 3 solution. Theisolated product was filtered washed with water. The product was crystallized fromethanol. M.P. 182°C, yield: 85.10 %. (C 25 H 28 ON 4 F 2 ; Required: C:68.47; H:6.44;N:12.78; Found: C: 68.45; H:6.43; N:12.75; %).Similarly, other Mannich bases were synthesized. The physical data arerecorded in Table no -6.[E] Biological screening of 1-N-(arylaminomethylamino)-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines:Biological screening were carried out as described in Part-I, Section-I. pageno-40. The zones of inhibition of test solutions are recorded in Graphical Chart no-6.104

Studies on Mannich BasesTABLE NO-6: PHYSICAL CONSTANTS OF 1-N-(ARYLAMINOMETHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.6a C 6 H 5 - C 24 H 26 N 4 F 2 408 159 72.94 13.72 13.716b 2-CH 3 -C 6 H 4 - C 25 H 28 N 4 F 2 422 182 75.29 13.26 13.246c 3-CH 3 -C 6 H 4 - C 25 H 28 N 4 F 2 422 169 69.36 13.26 13.246d 4-CH 3 -C 6 H 4 - C 25 H 28 N 4 F 2 422 184 64.71 13.26 13.246e 2-OCH 3 -C 6 H 4 - C 25 H 28 ON 4 F 2 438 190 67.54 12.78 12.756f 4-OCH 3 -C 6 H 4 - C 25 H 28 ON 4 F 2 438 182 85.10 12.78 12.756g 2-Cl-C 6 H 4 - C 24 H 25 N 4 F 2 Cl 442 201 76.42 12.65 12.646h 2-NO 2 -C 6 H 4 - C 24 H 25 O 2 N 5 F 2 453 218 67.32 15.44 15.426i 3-NO 2 -C 6 H 4 - C 24 H 25 O 2 N 5 F 2 453 232 79.17 15.44 15.426j 4-NO 2 -C 6 H 4 - C 24 H 25 O 2 N 5 F 2 453 195 76.85 15.44 15.42105

Studies on Mannich BasesGRAPHICAL CHART NO- 6 : BIOLOGICAL SCREENING OF 1-N-(ARYLAMINOMETHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.30ZONE OF INHIBITION IN mm25201510506a 6b 6c 6d 6e 6f 6g 6h 6i 6j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 19 20 21 18 19 23 17 22 20 24 23 22 24 0B.ce rus 21 17 16 22 23 19 14 21 18 22 22 23 21 0E .coli 20 22 16 19 21 18 13 17 23 15 21 21 23 0E .aerogen 17 20 16 21 15 19 15 22 20 19 19 20 22 0A.niger 19 21 17 22 19 15 21 23 17 19 0 0 0 23106

Studies on Mannich BasesPART-IIISECTION-II : BIOLOGICAL SCREENING STUDY OF 1-N-(ARYLAMINOMETHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger6b-(20) 6a-(21) 6a-(20) 6b-(20) 6b-(21)6c-(21) 6d-(22) 6b-(22) 6d-(21) 6d-(22)6f-(23) 6e-(23) 6e-(21) 6f-(19) 6g-(21)6h-(22) 6h-(21) 6i-(23) 6h-(22) 6h-(23)6i-(20) 6j-(22) 6i-(20)6j-(24) 6j-(19)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23107

Studies on Schiff’s BasesSTUDIES ON SCHIFF’S BASESINTRODUCTIONThe condensation of primary amines with carbonyl compounds was firstreported by Schiff 233 , and the condensation products are often referred to as Schiffbases. The general structure of these bases isR'R''NRwhere R, R’ and R” are H, alkyl, cyclohexyl, aryl, or heterocyclic radicals,which may be variously substituted. This condensation reaction, along with thechemical and physical properties of Schiff bases have been reviewed. 234-236 Schiffbases are also known as anils, imines, or azo methines.Various studies have been shown that the >C=N- group has considerablebiological importance, this can be substantiated by the fact that the possibility ofhaving a lone pair of electrons in either a π or an sp 2 hybridized orbital on trigonallyhybridized nitrogen in the >C=N- group; which is of fundamental chemical andbiological importance, and together with the variability of angles of hybridization itmakes possible the formation of nitrogen containing molecules with all the delicatedifferences in physicochemical properties necessary to produce the variousphenomena of life.In recent years, interest has also focused on aza-analogs such as Schiff’s basesderivatives which show a very similar pharmacological profile to classical. Over thepast few years, several lead-compounds have been developed. Schiff’s bases are alsoknown as schiff’s bases and they are well known intermediates for the preparation ofazetidinones, thiazolidinone, formazan, arylacetamide and many other entities ofpharamaceutical potential. These are the compounds containing characteristic–HC=N– group.Schiff’s bases are obtained mainly by warming the aldehyde & aromaticamine together. However, it is more convenient to work in a solvent such as alcohol,108

Studies on Schiff’s Basesdilute acetic acid or glacial acetic acid. Some time the reaction is aided by trace ofacid in other cases the hydrochloride of the amines can be used in the synthesis. Ingeneral Schiff’s bases do not react further with either of the reagents used in theirpreparation as do most of the other types of simple intermediates. Synthetic Schiff’sbase derivatives contribute in huge libraries owing to their wide applicability indifferent fields.SYNTHETIC ASPECTDifferent methods for the preparation of azomethine derivatives documentedin literature are described as under.1. A. J. Gallant et. al. 237 have prepared schiff’s bases by condensation ofequimolar quantity of 3,6-diformyl catechol and substituted o-phenylenediamine.OOHOOH+ORORH 2 NNH 2OOHOHNORNH 2OR2. General account of the summary of reaction of aldehydes with amine(aromatic or aliphatic) has been reviewed by M. S. Murray. 238R-CHO + R'-NH 2R-CH=N-R'3. A new one pot procedure for the generation of azomethine has beeninvestigated by R. J. Anderson and co-workers. 239OClR 1 N CH 3O OCOCl 2R 1R2+N CH 3R2OOR24. Strache 240 and Van Alphen 241 have prepared imine involves in two steps.a. Add. of the amine to the aldehyde gives aldol, which are rarely capable ofisolation.R-CHO + R'-NH R-CHOHNHR'2109

Studies on Schiff’s Basesb. The loss of water to give an imine (azomethine), this corresponds to the“crotonaldehyde stage” of the aldol condensation.R-CHO + R'-NH 2R-CH=N-R' + H 2 O5. Oddo and Tognacchini 242 have introduced the comparative rates of formationof Schiff‘s base from aniline & substituted aniline & aromatic aldehydeusing a cryscopic method follow the course of reaction.P. L. Beaulieu and co-workers 243 have synthesized (E)-N-phenyl methyleneglycine ethyl ester by the cyclocondensation of glycine ethyl ester hydrochloride,t-butylmethyl ether (TBME), benzaldehyde was added followed by anhydrousNa 2 SO 4 and triethylamineHCl.H 2NCOOEtPhCHOEt Et 3 NNa 2 SO 4 TBME 48hrs N COOEtTHERAPEUTIC IMPORTANCELiterature survey reveals that various Schiff’s bases reported as potentialdrugs and are known to possess broadn spectrum of biological activites.1. Antiviral 2442. Antifungal 2453. Antiparasitic 2464. Antibacterial 2475. Antipyretic 2486. Antiinflammatory 2497. Antitubercular 250Smalders et. al. 251 synthesized some new Schiff’s base as potential antitumoragents. Sharaf El-Din and Nabaweyal 252 have synthesized some Schiff’s basederivatives (I) having good antibacterial activity. Chohan et. al. 253 have synthesizedSchiff’s bases, which have been screened and compared for their antibacterial actionagainst bacterial species Escherichia coli, Pesudomonas aeruginose and Klebisellapneumoniase.110

Studies on Schiff’s BasesHOHONHOHOOHOHOR=3,4-OH,R=3,4-OH,3,4-NO3,4-NO 2 2( I )Schiff’s bases exhibit a wide range of pharmacological activities likeantifungal, antibacterial, antiviral, anti-inflammatory etc. R. H. Mehta et al. 254 havesynthesized coummarin schiff’s base derivatives (II) and examined for theirantibacterial activity. A. K. Khalafallah and M. E. Hassan. 255 have prepared somestyryl Schiff’s bases spiro derivatives as potential antibacterial and antifungal activity.HNOO( (II))Joydip Das et. al. 256 have synthesized trans-N-refinylidene-n-butylamine (III)which found stabillized in liposomes of phophatidylcholine. The rate of formation ofthe Schiff’s base is found to decrease with increasing cholesteral concentration in themembrane. V. M. Patel et.al. 257 have synthesized some new Schiff’s bases havinggood antibacterial activity.MeMe Me MeNBut(III)M. D. Deshmukh. and A. G. Doshi 258 prepared some new Schiff’s bases showgood antimicrobial activity against test organism S. aureus, E. coli, Saigella111

Studies on Schiff’s Basesdysenteridse and Salmonella typhi. Wang Yangang et. al. 259 have synthesizeddiazomethines having plant hormone activity. Das Arima et. al. 260 have preparedSchiff’s bases of aminohydroxy guanidine (SB-AHG5) and tested for antiviral activityagainst Herpes Simplex virus (HSV-1) and adenovirus (Ad-5) along with 11 otherheterocyclic SB-AHG5.S. Castellano et. al. 261 have prepared azomethine derivatives and evaluated invitro against several pathogenic fungi responsible for human disease. Holla B.Shivarama et. al. 262 have documented antibacterial, antifungal and herbicidal activityof Schiff’s base derivatives. Wang Yangsng and co-workers 263 have screened someSchiff’s bases having good plant hormone activity. Pascal Rothelst et. al. 264 havereported some new Schiff’s bases as antiparasitic agents.J. R. Dimmock et. al. 265 have reported Schiff’s bases as Cytotoxic agents. A.Adnan et. al. 266 have synthesized Schiff’s bases possessing significant antibacterialand antifungal activity.C. Alexandru et. al. 267 have synthesized Schiff’s bases, which have goodanalgesic and antipyretic properties. S. N. Pandeya et. al. 268 have synthesized Schiff’sbases showed 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 Salmonellal typhi and Vibrocholerae-0, (MIC 25-150 μg/ml).R. V. Chambhare et al. 269 have prepared some Schiff’s bases and tested fortheir antimicrobial activity. Holla B. Shivarama et. al. 270 have synthesized Schiff’sbases of (IV) having antibacterial and anti-inflammatory activity.RRClONHNNClSR=2-NOR=2-NO 2,4-NO 2,4-Br......etc.Cl2,4-NO 2,4-Br......etc.(IV)Ram Tilak et. al. 271 have synthesized some Schiff’s bases, thiazolidinones 4-triazolines, and formazones of 2-chloro phenothiazines and screened against112

Studies on Schiff’s Basescarrageenininduced edema in albino rats. The thiazolidinones showed promising antiinflammatoryactivity.Perumal Panneerselvam et al. 272 have been synthesized some novel Schiff’sbases by condensation of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones withdifferent aromatic aldehydes via cyclized intermediate 6,8-dibromo-2-phenylbenzoxazin-4-one. The synthesized compounds 3-(benzylideneamino)-6,8-dibromo-2-phenylquinazolin-4(3H)-one(V) were screened for anti-bacterial and anti-fungalactivity by paper disc diffusion technique.OBrNN=CH-RBrNC 6 H 5R=Aryl ( V )S. J. Wadher et. al. 273 have been synthesized Schiff’s bases of (VI) havingantibacterial and anti-fungal activity.RCHN SO 2NCHRR=Aryl( VI )Looking to the interesting properties of Schiff’s bases, we have synthesizedsome new Schiff’s bases, which have been described as under.SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLIDENEAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLMETHYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.113

Studies on Schiff’s BasesSECTION-ISYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLIDENEAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Schiff’s base derivatives represent one of the modest classes of biologicalactive agent which have been deeply studies during search on new potential drugs,these have been reported to be active as antimicrobial, antitubercular, anthelminticsetc. In view of getting to synthesized 1-N-arylideneamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines of Type (VII) have been synthesized by the condensation of 1-amino - 4 - [(4',4"- difluorodiphenyl) - methyl] - piperazine with different aromaticaldehydes in order to study their biodynamic behavior.FNNNRFType-VIIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.114

Studies on Schiff’s BasesIR SPECTRAL STUDY OF 1-N-[(4'''-METHOXYBENZYLIDENE)-AMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration Frequency in cm -1Ref.mode Observed ReportedC-H str.(asym.) 2948 2990-2850 474AlkaneC-H str. (sym.) 2881 2880-2860 "C-H def. (asym). 1450 1470-1435 "C-H def. (sym.) 1369 1390-1370 "C-H str. 3024 3090-3030 475Aromatic C=C str 1487 1600-1450 "C-H i.p. (def.) 1130 1300-1100 "Halide C-F str. 757 800-600 "Piperazine C-N str. 1323 1360-1310 "Ether C-O-C str. 1265 1280-1200 "Schiff’s baseC-N str. 1089 1220-1020 "C=N str. 1598 1612-1593 "115

Studies on Schiff’s BasesNMR SPECTRAL STUDY OF 1 - N - [(4'''- METHOXYBENZYLIDENE) -AMINO]- 4 - [(4',4" -DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.Fh'i'feNNdhijgNj'f'e'cbc'b'kFk'OCH3aInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.50-2.59 4H doublet C-H (ff’)2 2.73-2.77 4H doublet C-H (ee’)3 3.75 3H singlet Ar-OCH 3 (a)4 5.20 1H singlet C-H (g)5 6.89-6.89 4H doublet Ar-H (hh’, kk’)6 7.08-7.10 2H doublet Ar-H (bb’)7 7.14-7.28 4H triplet Ar-H (ii’, jj’)8 7.37-7.44 2H doublet Ar-H (cc’)9 8.11 1H singlet C-H (d)116

Studies on Schiff’s BasesMASS SPECTRAL STUDY OF 1-N-[(4'''-METHOXYBENZYLIDENE)-AMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.117

Studies on Schiff’s BasesMASS FRAGEMENT STUDY OF 1-N-[(4'''-METHOXYBENZYLIDENE)-AMINO]-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.F+oF+oOCH 3OCH 3F+oOCH 3+oH NNm/z = 288FN H 2NNm/z = 303FNNm/z = 219NH+oNNm/z = 327NF+oN H 2NH 2m/z = 137FFOm/z = 219FFNCH 3NH 3CFFNH 3 CN+om/z = 275+om/z = 421C H 3NHNNm/z = 317FH Nm/z = 86NH+oOCH 3Nm/z = 150+oNH 2Fm/z = 96+oC H 3Om/z = 108+oNm/z = 209NF+oNH 2NNNHCH 2m/z = 113+oFF+oC H 3C H 3m/z = 204NH 3 CNO+om/z = 206118

Studies on Schiff’s BasesREACTION SCHEMEFNNHFNaNO 2+ HClF0-5 0 CN N NOFFLiAlH 4N N NH 2R-CHOFFCon.H 2 SO 4N N NRType - VIIFR = Aryl119

Studies on Schiff’s BasesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLIDENEAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.[A]Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B]Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4'''-methoxybenzylidene)-amino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine(7e):A mixture of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine (3.03gm,0.01M) and 4-methoxybenzaldehyde (1.36 gm, 0.01M) dissolved in ethanol (20 ml) inpresence of catalytic amount of concentrated sulphuric acid (0.2 ml).The reactionmixture was refluxed for 8 hrs. The contents were cooled and poured in crushed iceproduct was isolated and re-crystallized from ethanol. Yield: 76.54%, M.P. 146 o C.(C 25 H 25 ON 3 F 2 ; Required: C: 71.24; H: 5.98; N: 9.97; Found: C: 71.20; H: 5.95; N:9.94%).Similarly, other Schiff’s bases were prepared. The physical constants arerecorded in Table No-7.[D] Biological Screening of 1-N-arylidieneamino-4-[(4',4"-difluorodiphenyl) -methyl]-piperazines:Biological Screening was carried out as described in Part-I, Section-I, Pageno-40. The zone of inhibition of the test solution are recorded in Graphical Chart No-7.120

Studies on Schiff’s BasesTABLE NO - 7 : PHYSICAL CONSTANTS OF 1-N-ARYLIDENEAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.7a C 6 H 5 - C 24 H 23 N 3 F 2 391 214 62.21 10.73 10.707b 2-OH-C 6 H 4 - C 24 H 23 ON 3 F 2 407 187 66.00 10.31 10.277c 4-OH-C 6 H 4 - C 24 H 23 ON 3 F 2 407 139 76.29 10.31 10.277d 2-OCH 3 -C 6 H 4 - C 25 H 25 ON 3 F 2 421 165 75.87 9.97 9.947e 4-OCH 3 -C 6 H 4 - C 25 H 25 ON 3 F 2 421 146 76.54 9.97 9.947f 2-Cl-C 6 H 4 - C 24 H 22 N 3 F 2 Cl 425 132 60.47 9.87 9.857g 4-F-C 6 H 4 - C 24 H 22 N 3 F 3 409 178 55.74 10.26 10.227h 2-NO 2 -C 6 H 4 - C 24 H 22 O 2 N 4 F 2 436 187 59.25 12.84 12.807i 3-NO 2 -C 6 H 4 - C 24 H 22 O 2 N 4 F 2 436 196 60.12 12.84 12.807j C 4 H 3 O - C 22 H 21 ON 3 F 2 381 193 65.00 11.02 10.97121

Studies on Schiff’s BasesGRAPHICAL CHART NO -7 : BIOLOGICAL SCREENING OF 1-N-ARYLIDENEAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.30ZONE OF INHIBITION IN mm25201510507a 7b 7c 7d 7e 7f 7g 7h 7i 7j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 19 22 19 23 17 24 14 20 24 23 23 22 24 0B.cerus 14 20 22 13 23 16 22 15 22 14 22 23 21 0E .coli 19 20 14 22 16 23 17 19 21 14 21 21 23 0E .aerogen 16 14 20 14 19 21 17 16 20 22 19 20 22 0A.niger 20 17 21 17 23 18 21 14 22 15 0 0 0 23122

Studies on Schiff’s BasesPART-IVSECTION - I : BIOLOGICAL SCREENING STUDY OF 1-N-ARYLIDENEAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger7b-(22) 7b-(20) 7b-(20) 7c-(20)7c-(21)7d-(23) 7c-(22) 7d-(22) 7e-(19) 7e-(23)7f-(24) 7e-(23) 7f-(23) 7f-(21) 7g-(21)7h-(20) 7g-(22) 7i-(21) 7i-(20) 7i-(22)7i-(24) 7i-(22) 7j-(22)7j-(23)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23123

Studies on Schiff’s BasesSECTION-IISYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLMETHYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Piperazine derivatives are associated with wide therapeutic activities likeantimicrobial, antitubercular, anthelmintics, anticancer etc. These finding promptedus to synthesize 1-N-aryl methylamino - 4 - [(4', 4"- difluorodiphenyl) - methyl] -piperazines of Type (VIII) bearing piperazine moiety obtained by selectivereduction of (imine group) Schiff’s bases of 1 - N - arylideneamino - 4 - [(4', 4"-difluorodiphenyl) - methyl] -piperazines of Type (VII) with sodium borohydride(NaBH 4 ).FNNNHRFType-VIIIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.124

Studies on Schiff’s BasesIR SPECTRAL STUDY OF 1 - N - [(4''' - METHOXYPHENYL) - METHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.FN N NHCH 3OFInstrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibration Frequency in cm -1Ref.mode Observed ReportedC-H str.(asym.) 2910 2990-2850 474AlkaneC-H str. (sym.) 2837 2880-2860 "C-H def. (asym). 1454 1470-1435 "C-H def. (sym.) 1396 1390-1370 "Alkene -CH 2 str. 2655 2850-1790 "C-H str. 3033 3090-3030 475Aromatic C=C str. 1496 1600-1450 "C-H i.p. (def.) 1197 1300-1100 "Halide C-F str. 759 800-600 "Piperazine C-N str. 1361 1360-1310 "Ether C-O-C str. 1250 1280-1200 "Schiff’s baseC-N str. 1606 1650-1550 "N-H bend. 1522 1650-1510 "Sec. amine N-H str. 3330 3500-3100 "125

Studies on Schiff’s BasesNMR SPECTRAL STUDY OF 1-N-[(4'''-METHOXYPHENYL)-METHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.Fi'ijklj'g'h Ngk'f'fNeNHdc'cb'baCH3OFl'Internal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.30-2.38 4H doublet C-H (gg’)2 2.61-2.67 4H doublet C-H (ff’)3 3.70 3H singlet Ar-OCH 3 (a)4 4.01 2H singlet C-H (d)5 5.10 1H singlet C-H (h)6 6.93-6.96 2H doublet Ar-H (bb’)7 7.04-7.06 4H triplet Ar-H (ii’, ll’)8 7.18-7.27 2H doublet Ar-H (cc’)9 7.39-7.48 4H triplet Ar-H (jj’, kk’)10 8.10 1H singlet N-H (e)126

Studies on Schiff’s BasesMASS SPECTRAL STUDY OF 1-N-[(4'''-METHOXYPHENYL)-METHYLAMINO)-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE.127

Studies on Schiff’s BasesMASS FRAGEMENT STUDY OF 1 - N - [(4'''- METHOXYPHENYL) - METHYLAMINO) - 4 - [(4', 4"- DIFLUORODIPHENYL) -METHYL]-PIPERAZINE.F+oF+oC H 3OF+oC H 3O+o+oH NFm/z = 96+oN HH N+oNm/z = 288FN H 2NNm/z = 303FH 2 Nm/z = 137m/z = 204FC H 3NH 3 CN Hm/z = 208N H 2Fm/z = 219+oFm/z = 86FFF+oC H 3C H 3Nm/z = 275F+oC H 3FN N N Hm/z = 423OC H 3FC H 3N HNNm/z = 317FH NC H 3NNN Hm/z = 235+oNN Hm/z = 221+oOm/z = 108NC H 3OC H 3O+oNN Hm/z = 329C H 3OF+oH NN N HFN N N Hm/z = 387+oN N N Hm/z = 393+oOC H 3+oN+om/z = 115C H 3Fm/z = 194NH128

Studies on Schiff’s BasesREACTION SCHEMEFNNHFFNaNO 2 + HCl0-5 0 CN N NOFFLiAlH 4N N NH 2FR-CHOCon.H 2 SO 4FFNaBH 4Type - VIII R = ArylN N NRN N NHRFF129

Studies on Schiff’s BasesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-ARYLMETHYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.[A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4'''-methoxybenzylidene)-amino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-IV, Section-I (C), on page no-120[D] Synthesis of 1 - N - [(4'''-methoxyphenyl) - methylamino] - 4 - [(4',4"-difluorodiphenyl)-methyl]-piperazine:Sodium borohydride (0.57gm, 0.015M) was added to a methanolic solution of1 - N - [(4'''- methoxybenzylidene) - amino] - 4 - [(4',4"- difluorodiphenyl) - methyl] -piperazine (4.21gm, 0.01M) over a period of 30 minutes at temperature 5-10 o C withconstant stirring. The reaction mixture was kept over night at room temp withconstant stirring. The excess sodium borohydride was neutralized by adding waterand the product was extracted with ether. The ether layer was washed with wateruntill become neutral, then dried over anhydrous Na 2 SO 4 and finally the etherwas evaporated to give aminomethyl derivatives. Yield: 82.00%, M.P. 175°C.(C 25 H 27 ON 3 F 2 ; Required: C: 70.90; H: 6.43; N: 9.92; Found: C: 70.87; H: 6.39; N:9.89 %).Similarly, other methylamino derivatives were prepared. The physicalconstants are recorded in Table No-8.[E] Biological Screening of 1 - N - arylmethylamino - 4 - [(4',4"-difluorodiphenyl)- methyl]-piperazines:Biological Screening was carried out as described in Part-I, Section-I, Pageno-40. The zone of inhibition of the test solution are recorded in Graphical Chart No-8.130

Studies on Schiff’s BasesTABLE NO - 8 : PHYSICAL CONSTANTS OF 1-N-ARYLMETHYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.8a C 6 H 5 - C 24 H 25 N 3 F 2 393 186 72.28 9.66 9.628b 2-OH-C 6 H 4 - C 24 H 25 ON 3 F 2 409 171 69.40 10.26 10.228c 4-OH-C 6 H 4 - C 24 H 25 ON 3 F 2 409 179 73.49 10.26 10.228d 2-OCH 3 -C 6 H 4 - C 25 H 27 ON 3 F 2 423 157 65.38 9.92 9.898e 4-OCH 3 -C 6 H 4 - C 25 H 27 ON 3 F 2 423 175 82.00 9.92 9.898f 2-Cl-C 6 H 4 - C 24 H 24 N 3 F 2 Cl 427 127 80.47 9.82 9.858g 4-F-C 6 H 4 - C 24 H 24 N 3 F 3 411 108 85.11 10.21 10.198h 2-NO 2 -C 6 H 4 - C 24 H 24 O 2 N 4 F 2 438 161 69.87 12.78 12.758i 3-NO 2 -C 6 H 4 - C 24 H 24 O 2 N 4 F 2 438 117 74.12 12.78 12.758j C 4 H 3 O - C 22 H 23 ON 3 F 2 383 172 78.00 10.96 10.94131

Studies on Schiff’s BasesGRAPHICAL CHART NO - 8 : BIOLOGICAL SCREENING OF 1-N-ARYLMETHYLAMINO-4-[(4',4"-DIFLUORODIPHENYL)-METHYL]-PIPERAZINES..30ZONE OF INHIBITION IN mm25201510508a 8b 8c 8d 8e 8f 8g 8h 8i 8j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 15 22 18 23 17 21 19 14 24 23 23 22 24 0B.cerus 14 22 16 21 15 20 16 23 13 20 22 23 21 0E .coli 19 23 15 22 16 20 15 15 17 21 21 21 23 0E .aerogen 17 20 14 19 16 22 15 21 18 22 19 20 22 0A.niger 19 22 16 23 15 17 17 21 18 21 0 0 0 23132

Studies on Schiff’s BasesPART-IVSECTION - II : BIOLOGICAL SCREENING STUDY OF 1 - N - ARYLMETHYLAMINO - 4 - [(4', 4"- DIFLUORODIPHENYL) -METHYL]-PIPERAZINES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger8b-(22) 8b-(22) 8b-(23) 8b-(20) 8b-(22)8d-(23) 8d-(21) 8d-(22) 8d-(19) 8d-(23)8f-(21) 8f-(20) 8f-(20) 8f-(22) 8h-(21)8i-(24) 8h-(23) 8j-(21) 8h-(21) 8j-(21)8j-(23) 8j-(20) 8i-(18)8j-(22)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23133

Studies on 4-ThiazolidinonesSTUDIES ON 4-THIAZOLIDINONESINTRODUCTIONThiazolidinones, which belong to an important group of heterocycliccompounds, have been extensively explored for their application in the field ofmedicine. Thiazolidinones, with a carbonyl group at position 2-(I), 4-(II), on 5-(III) havebeen subjects of extensive study in the field of 4-Thiazolidinones. Numerous reportshave appeared in the literature which high light their chemistry and use.4HN3O4HN34HN351S2O51S2O51S2( I ) ( II ) ( III )4-Thiazolidinones derivatives of thiazolidinone with carbonyl group at 4-position(II) substituent in 2,3- and 5 position may be varied but the greatest different instructure and properties is exerted by the group attached to carbon atom at the 2-possition and to N atom at the 3-position. V. H. Shah et. al. 274 have beensynthesized 4-thiazolidinones derivatives in thymol nucleus. The cyclic structurewas assigned after recognisation of mercapto acetic acid as primary products ofhydrolysis of 3-phenyl-2 -phenyl-amino-4-thiazolidinones. 275The chemistry of 4-thiazolidinones was reviewed in depth by F. C. Brown 276in 1962 and G. R. Newkome and A. Nayak 277 in 1977.MECHANISMThe reaction mechanisms of the formation of 4-thiazolidinones are wellstudied by A. Verma et.al. 278 The reaction proceeds by of the mercapto acetic acid134

Studies on 4-Thiazolidinonesupon the C=N group, with the HS-CH 2 -COOH adding to the carbon atom followedby the capture of a proton by nitrogen and subsequent cyclization.R 2R 11 NH 2OR 3Step-1-H -H 22 OR 11 N CR 2R 3OOHSHR 4R 5 Step-2R 1RN2 R 3 SOR 5R 4Step-3-H -H 22 OR 3 R 2R 1 HN CHOOSR 5R 4 In there reaction, the uncyclised intermidiate is formed in several cases.The uncyclised product has been isolated 279 , phosphorous pentoxide in dioxane wasused for subsequent cyclisation of certain uncyclised products. 280 In may instance4-thiazolidinones can conveniently be prepared by refluxing the mixture of thethioglycolic acid and schiffs bases in benzene 281 , dry ether 282 or ethanol. 283The nucleophilic attach of mercapto acetic acid anion on carbon ofazomethine, which has got possitive character while nitrogen has negativecharacter is evidenced, simultaneously removal of water as it form in reaction, helps,in condensation and determination of the reaction time.SYNTHETIC ASPECT4-Thiazolidinones are synthesized either by cyclization of acyclic compoundsor by interconversion among appropriately substituted thiazolidinone derivatives.α-Mercapto alkanoic acids have been extensively used for the synthesis of4-thiazolidinones.135

Studies on 4-ThiazolidinonesRNHR 1++ HSR 2R 3COOHHNRR 1SR 3R 2COOHR = Alkyl or ArylR 1 = Aryl or HeterocyclicR 2 = H or AlkylR 3 = H or AlkylR 2 ,R 3 = ArylideneOR 3R2HNSR 1The substituted α-mercapto alkanoic acid reacts conveniently with schiffsbases to give a variety of 2-substituted-4-thiazolidinones. 284-286THERAPEUTIC IMPORTANCEThe 4-Thiazolidinones ' subsituted at 2- and 3-position showed a wide variety ofbiologically activity. The frequent ocurrence of group - NH - CS - NH - or itstautomer in compounds possess and evaluated in vitro tuberculostatic activity byE. Frolich et al. 2871. Analgesic 2882. Antibacterial 289,2903. Antidiabetic 2914. Antifungal 292-2945. Anti HIV and anti cancer 2956. Anti microbial 296,2977. Antiulcer 298,2998. Anti tumor 3009. Anti tubuercular 301,30210. Anti viral 30311. Anthelmintics 304,30512. Cardiovascular 30613. Herbicidal 30714. Hypnotic 308-310 136

Studies on 4-Thiazolidinones15. Insectidal 31116. Mosquito repellent 31217. Local anaesthetic 313K. Mogliaiah and Co-workers 314,315 isolated some 4-thiazolidinonesderivativies and tested their antibacterial activity. H. Y. Hassan et. al. 316 hasprepared 2-amino-4-thiazolidinones which have been found to possessantimicrobial activity. G. S. Gadaginamath et.al. 317 also prepared thiazolidinonesderivatives, as antimicrobial agent.R. S. Lodhi and co-workers 318 have been synthesized and studiedantimicrobial, anti-inflammatory and analgesic activity of 4-thiazolidinone andarylidene derivatives (IV).NNONHNOSZR = (Un) Substituted arylZ = H 2Z = CH 2 R 2R 1R 1 = Substituted aryl( IV )G. Bhawana et. al. 319 have been synthesized thiazolidinonederivatives and compared their anti-inflammatory potency, ulcerogenic liability,cardiovascular and CNS effect. R. P. Pawar and co-workers 320 reported synthesis andin vitro antibacterial activity of some 4-thiazolidinone derivatives. Inother study, some thiazolidinone derivatives have been found to be promisingantibacterial agent. 321 A. J. Baxi et. al. 322 have been synthesized 4-thiazolidinonederivatives and also evaluated antimicrobial activity.Morever, Albuquerque and co-workers 323 have prepared 4-thiazolidinoneswhich show antidiabetic and antiinflammatory activity. Tagami and co-worker 324 havesynthesized 4-thiazolidinone derivatives as allergy inhibitor. M. Siddique et. al. 325have prepared substituted thiazolidinones and reported their antibacterial,antifungal, antithyroid and amoebicidal properties(V).137

Studies on 4-ThiazolidinonesR 1OR 2SNR 5R 4R 3R 1 = OHSR 2 ,R 4 ,R 5 = H( V )R 3 = MeH. H. Parekh and et. al. 326 have been synthesized some new thiazolidinones asantimicrobial agent (VI).RNOSCH 3C H 3NCl( VI ) R=ArylH. S. Joshi et. al. 327 have synthesis microwave assited 4-thiazolidinonesand reported as biological active agent.K. R. Desai et.al. 328 have been synthesized some new 4-thiazolidinones asantimicrobial agent (VII).ORCH 3NCH 3NS CSNH 3 CN( VII ) R= Aryl138

Studies on 4-ThiazolidinonesR. K. Rawal et al. 329 have reported a series of compounds bearing isothioureaor thiourea functional group and have shown high anti-HIV-1 activity. Furthermore, aseries of 2-aryl-3-heteroaryl-1,3-thiazolidine-4-ones was also reported by thisgroup( IX ).CHOOSN+NH 2+RSHCH 2 COOHToluene, RefluxNSNSRR=Aryl( IX )C. J. Hobbs et. al. 330 have synthesized some new N-type (Cav2.2) calciumchannel blockers derived from the ‘hit’ structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one and its 2-[4-(4-bromophenyl) pyridin-3-yl]-3-isobutyl analogues( X ).CH 3OROBrSHCH 2 COOHNSBrNIsobutylamine,C 6 H 6 , 70 °CH 3 C( X )NZhong-Zheng Zhou et. al. 331 have prepared a one-pot liquid-phasecombinatorial synthesis of 2-(4-oxo-4H-1-benzopyran-3-yl)-4-thiazolidinones bearingdiverse substituents at the 3-position under microwave irradiation using 3-formylchromone, primary amine, and mercaptoacetic acid as reactants( XI ).139

Studies on 4-ThiazolidinonesROOO++HNH 2RNa 2 SO 4 , PTSAMWR=Aryl ( XI )OOSNOS. V. Bhandari et.al. 332 have been synthesized thiazolidinonederivatives and tested for electrocardiographic, antiarrhythmic,vasorelaxing and antihypertensive activity as well as for in-vitro nitricoxide (NO) releasing ability (VIII).NNSRHOOHNCONHNHCOCH 2 ONO 2( VIII ) R= Substituted phenylIn view of getting better therapeutic activities showed by 4-thiazolidinones, toprompted us to synthesize included piperazine molecule in 4-thiazolidinones moiety,which have been described as under.140

Studies on 4-ThiazolidinonesSECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONES.SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING OF 2-ARYL-3-N-{4'-[(4'',4"'-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONES.SECTION-III : SYNTHESIS AND BIOLOGICAL SCREENING OF 2-ARYL-3-N-{4'-[(4'',4"'-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONES.141

Studies on 4-ThiazolidinonesSECTION - ISYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONES.4-Thiazolidinone derivatives represent one of the most active classes ofcompounds possessing a wide spectrum of biological activities, such as significant invitro activity against DNA and RNA viruses including polio viruses, hypnotic,sedative, analgesic, diuretic, antitubercular, anticonvulsant, antifungal, antibacterial,activity etc. These valid observations led us to synthesize some new 4-thiazolidinonederivatives. 2 - Aryl - 3 - N - {4'-[(4", 4'''- difluorodiphenyl) - methyl] - piperazine-1'-yl}-5-H -4-thiazolidinones of Type (IX) have been synthesized by theheterocyclization of Schiff’s bases of 1-N-arylideneamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines of Type (VII) with thioglycolic acid.FRNNNSOFType-IXR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.142

Studies on 4-ThiazolidinonesIR SPECTRAL STUDY OF 2 -(4''''- METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibretion Frequency in cm -1 Ref.Observed ReportedmodeC-H str.(asym.) 2947 2990-2850 474AlkaneC-H str. (sym.) 2885 2880-2860 "C-H def. (asym. 1446 1470-1430 "C-H def. (sym.) 1377 1395-1370 "Alkene -CH 2 str. 2812 2850-1790 "C-H str. 3045 3090-3030 "Aromatic C=C str 1519 1600-1450 "C-H i.p. (def.) 1197 1300-1100 "Halide C-F str. 779 800-600 475Piperazine C-N str. 1327 1360-1310 "Ether C-O-C str. 1274 1280-1200 "C-N str. 1047 1220-1020 "Thiazolidinone C=O str. 1677 1710-1650 "C-S-C str. 713 750-600 "143

Studies on 4-ThiazolidinonesNMR SPECTRAL STUDY OF 2 -(4''''-METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONE.aH 3 COFijkli'j'hk'Ngg'bff'cNb'c'dSN e'HHO eFl'Internal Standard: TMS; Solvent: CDCl3; 3 Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.49-2.57 4H doublet C-H (gg’)2 2.61-2.66 4H doublet C-H (ff’)3 2.85-2.95 1H quartet Ar-H (e’)4 3.26-3.44 1H quartet Ar-H (e)5 3.82 3H singlet Ar-OCH 3 (a)6 5.00 1H singlet C-H (h)7 5.90 1H singlet Ar-H (d)8 6.85-6.87 2H doublet Ar-H (bb’)9 7.00-7.10 4H ddoublet Ar-H (ii’, ll’)10 7.26-7.28 2H doublet Ar-H (cc’)11 7.47-7.53 4H ddoublet Ar-H (jj’, kk’)144

Studies on 4-ThiazolidinonesMASS SPECTRAL STUDY OF 2 -(4''''-METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONE.145

Studies on 4-ThiazolidinonesMASS FRAGEMENT STUDY OF 2 - (4''''- METHOXYPHENYL) - 3 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONE.F+oF+oC H 3OC H 3O+oOCH 3F+oOFCH 3+om/z = 137NH 2H NNm/z = 288FN H 2NNm/z = 303F+oC H 3N NF m/z = 108 H 3 Cm/z = 280 OH 3 C OSNNNHm/z = 329N H 2Fm/z = 219F+o+oFm/z = 317CH 3NH 3Cm/z = 275+oFNNm/z = 495NOSC H 3NHNNC H 3OFH NN H+oFm/z = 86Fm/z = 96+oFF+om/z = 204F+oNN HH NOm/z = 194 m/z = 103SH N+oN Nm/z = 187OS+oFNNN N+ m/z = 459 OoH 3 C Om/z = 401NNOS+oS146

Studies on 4-ThiazolidinonesREACTION SCHEMEFNNHFFNaNO 2 + HCl0-5 0 CN N NOFFLiAlH 4N N NH 2FR-CHOCon.H 2 SO 4FFRN N NHSCH 2 COOHNNNSROFFType - IXR = Aryl147

Studies on 4-ThiazolidinonesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONES.[ A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4'''-methoxybenzylidene)-amino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-IV, Section-I (C), on page no-120[D]Synthesis of 2 -(4''''-methoxyphenyl)-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-H-4-thiazolidinone(9e):A mixture of 1 - N -[(4'''- methoxybenzylidene)- amino] - 4 - [(4',4"- difluorodiphenyl)-methyl]-piperazine (4.21gm, 0.01M) in benzene (25 ml) was taken, Deanstark apparatus was attached to it and thioglycolic acid (0.92 gm, 0.01M) in benzenewas added slowly. Then it was refluxed for 15 hrs, during the course of the reactionthe water was removed continuously. The benzene was distilled off to get thethiazolidinones. The solid product was filtered, dried and recrystallized from absolutealcoho l. Yield: 82 %, M.P.176 o C.(C 27 H 27 O 2 N 3 F 2 S; Required: C: 65.44; H: 5.95; N: 8.48; Found : C:65.40; H: 5.92; N:8. 45 %).Similarly, other 4-thiazolidinones were prepared. The physical constants arerecorde d in Table No-9.[E] Biological Screening of 2 -aryl-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-H-4-thiazolidinones:Biological Screening were carried out as described in Part-I, Section-1 pageno-40. The zones of inhibition of test solution are recorded in Graphical Chart No-9.148

Studies on 4-ThiazolidinonesTABLE NO - 9 : PHYSICAL CONSTANTS OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONES.M.P. YieldSr. No. R Molecular Formula M.W. 0 C %Calcd.%of NitrogenFound.9aC 6 H 5 - C 26 H 25 ON3F2S 465 142 65.15 9.03 9.009b 2-OH-C6H4- C26H 25 O2N3F2S 481 117 69.47 8.73 8.699c 4-OH-C6H4 - C26H 25 O2N3F2S 481 179 61.32 8.73 8.699d9e2-OCH3-C6H4 - C 27 H 27 O2N3F2S 495 135 70.25 8.48 8.454-OCH3-C6H4 - C 27 H 27 O2N3F2S 495 176 82.00 8.48 8.459f 2-Cl-C 6 H4 - C26H 24 ON3F2SCl 500 162 72.85 8.40 8.369g 4-F-C 6 H4 - C26H 24 ON3F3S 483 108 64.36 8.69 8.669h9i9j2-NO2-C6H4 - C 26 H 24 O3N4F2S 510 127 78.88 10.97 10.953-NO2-C6H4 - C 26 H 24 O3N4F2S 510 134 76.48 10.97 10.95C4H3 O - C 24 H 23 O2N3F2S 455 182 69.51 9.22 9.18149

Studies on 4-ThiazolidinonesGRAPHICAL CHART NO - 9 : BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL] -PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONES.30ZONE OF INHIBITION IN mm25201510509a 9b 9c 9d 9e 9f 9g 9h 9i 9j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 21 15 20 23 17 24 14 22 17 23 23 22 24 0B.cerus 16 22 14 21 14 23 20 15 22 17 22 23 21 0E .coli 18 21 16 23 19 17 20 19 22 16 21 21 23 0E .aerogen 19 13 18 15 20 16 22 14 21 15 19 20 22 0A.niger 17 22 18 20 23 19 15 18 22 21 0 0 0 23150

Studies on 4-ThiazolidinonesPART-VSECTION - I : BIOLOGICAL SCREENING STUDY OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-H-4-THIAZOLIDINONES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger9a-(21) 9b-(22) 9b-(21) 9a-(19) 9b-(22)9c-(20) 9d-(21) 9d-(23) 9c-(18) 9e-(23)9d-(23) 9f-(23) 9g-(20) 9e-(20) 9i-(22)9f-(24) 9g-(20) 9i-(22) 9g-(22) 9j-(21)9h-(22) 9i(22) 9i-(21)9j-(23)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23151

Studies on 4-ThiazolidinonesSECTION - IISYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONES.4-Thiazolidinone derivatives represent one of the most active classes ofcompounds possessing a wide spectrum of biological activities, such as significant invitro activity against DNA and RNA viruses including polio viruses, hypnotic,sedative, analgesic, diuretic, antitubercular, anticonvulsant, antifungal, antibacterial,activity etc. These valid observations led us to synthesize some new 4-thiazolidinonederivatives. 2-Aryl-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]- piperazine-1'-yl}-5-methyl - 4 -thiazolidinones of Type (X) have been synthesized by theheterocyclization of Schiff’s bases of 1-N-arylideneamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines of Type (VII) with thiolactic acid.FRNNNSOCH 3FType-XR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.152

Studies on 4-ThiazolidinonesIR SPECTRAL STUDY OF 2 -(4''''-METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibretion Frequency in cmRef.Observed ReportedmodeAlkane C-H str.(asym.) 2910 2990-2850 474C-H str. (sym.) 2879 2880-2860 "C-H def. (asym. 1442 1470-1430 "C-H def. (sym.) 1386 1395-1370 "Aromatic C-H str. 3072 3090-3030 "C=C str 1506 1600-1450 "C-H i.p. (def.) 1272 1300-1100 "Halide C-F str. 808 800-600 475Piperazine C-N str. 1323 1360-1310 "Ether C-O-C str. 1226 1280-1200 "C-N str. 1155 1220-1020 "Thiazolidinone C=O str. 1652 1710-1650 "C-S-C str. 701 750-600 "-1153

Studies on 4-ThiazolidinonesNMR SPECTRAL STUDY OF 2 -(4''''-METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONE.FjklmFj'k'il'm'haH 3 CbOcgN N Nh'g'Ob'dc'SefCH 3Internal Standard: TMS; Solvent: CDCl3; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 1.36-1.38 3H doublet Ar-CH 3 (f)2 2.48-2.53 4H doublet C-H (hh’)3 2.57-2.60 4H doublet C-H (gg’)4 3.51-3.60 1H quartet Ar-H (e)5 3.80 3H singlet Ar-OCH 3 (a)6 5.19 1H singlet C-H (i)7 5.93 1H singlet Ar-H (d)8 7.02-7.05 2H doublet Ar-H (bb’)9 7.37-7.41 4H doublet Ar-H (jj’, mm’)10 7.51-7.54 2H doublet Ar-H (cc’)11 7.85-7.89 4H triplet Ar-H (kk’, ll’)154

Studies on 4-ThiazolidinonesMASS SPECTRAL STUDY OF 2 -(4''''-METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONE.155

Studies on 4-ThiazolidinonesMASS FRAGEMENT STUDY OF 2 - (4''''- METHOXYPHENYL) - 3 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONE.F+oF+oCH 3 OCH 3+oF+oC H 3OCOCH 3NH 3CH 3F+oFH NH NH 3 Cm/z = 137ONH 2+om/z = 108m/z = 275m/z = 96+o+om/z = 86Nm/z = 288F+oN HC H 3C H 3NNFSOm/z = 294N H 2H 3 C OH NCH 3+oNNm/z = 303FFSCH 3Om/z = 117FNOCH 3SH NN NH N S+oH 3 CFm/z = 307OF m/z = 204 OCH 3m/z = 223m/z = 509+o +oNNNOm/z = 403SNNOSC H 3CH 3NNC H 3NONHSNFH 2 Nm/z = 219H 3 C O+S oNN NCH 3H 3 Cm/z = 473OOCH 3m/z = 321+oNFm/z = 317+oF+oFF156

Studies on 4-ThiazolidinonesREACTION SCHEMEFNNHFFNaNO 20-5 0 C+ HClN N NOFFLiAlH 4N N NH 2R-CHOCon.H 2 SO 4FFFN N NHSCH COOHCH 3Type - X R = ArylNNNRSROCH 3FF157

Studies on 4-ThiazolidinonesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONES.[ A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4'''-methoxybenzylidene)-amino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-IV, Section-I (C), on page no-120[D]Synthesis of 2 -(4''''-methoxyphenyl)-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-methyl-4-thiazolidinone(10e):A mixture of 1- N - [(4'''- methoxybenzylidene)- amino]- 4 -[(4',4"-difluorodiphenyl)-methyl]-piperazine (4.21gm, 0.01M) in benzene (25 ml) was taken, Deanstark apparatus was attached to it and thiolactic acid (1.06 gm, 0.01M) in benzenewas added slowly. Then it was refluxed for 15-16 hrs, during the course of thereaction the water was removed continuously. The benzene was distilled off to get thethiazolidinones. The solid product was filtered, dried and recrystallized from absolutealcoho l. Yield: 78.03 %, M.P.116C.O 28. 23 %).N 3 F 2 S; Required: C: 65.99; H: 5.74; N: 8.25; Found : C:65.97; H: 5.71; N:(C 28 H 29dSimilarly, other 4-thiazolidinones were prepared. The physical constants arerecorde in Table No-10.[E] Biological Screening of 2 -aryl-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-methyl-4-thiazolidinones:Biological Screening were carried out as described in Part-I, Section-1 pageno-40. The zones of inhibition of test solution are recorded in Graphical Chart No-10.158

Studies on 4-ThiazolidinonesTABLE NO -10 : PHYSICAL CONSTANTS OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE - 1' -YL}-5-METHYL-4-THIAZOLIDINONES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.10a C 6 H 5 - C 27 H 27 ON 3 F 2 S 479 122 69.54 8.76 8.7410b 2-OH-C 6 H 4 - C 27 H 27 O 2 N 3 F 2 S 495 96 70.71 8.48 8.4510c 4-OH-C 6 H 4 - C 27 H 27 O 2 N 3 F 2 S 495 129 64.00 8.48 8.4510d 2-OCH 3 -C 6 H 4 - C 28 H 29 O 2 N 3 F 2 S 509 145 77.29 8.25 8.2310e 4-OCH 3 -C 6 H 4 - C 28 H 29 O 2 N 3 F 2 S 509 116 78.03 8.25 8.2310f 2-Cl-C 6 H 4 - C 27 H 26 ON 3 F 2 SCl 514 132 82.85 8.17 8.1310g 4-F-C 6 H 4 - C 27 H 26 ON 3 F 3 S 497 158 74.69 8.44 8.4010h 2-NO 2 -C 6 H 4 - C 27 H 26 O 3 N 4 F 2 S 524 141 71.52 10.68 10.6510i 3-NO 2 -C 6 H 4 - C 27 H 26 O 3 N 4 F 2 S 524 134 74.35 10.68 10.6510j C 4 H 3 O - C 25 H 25 O 2 N 3 F 2 S 469 122 67.43 8.95 8.92159

Studies on 4-ThiazolidinonesGRAPHICAL CHART NO - 10 : BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL] -PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONES.30ZONE OF INHIBITION IN mm252015105010a 10b 10c 10d 10e 10f 10g 10h 10i 10j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 14 22 19 17 21 22 17 23 22 14 23 22 24 0B.cerus 19 22 17 23 20 22 19 21 16 22 22 23 21 0E .coli 21 14 19 23 22 16 20 15 22 17 21 21 23 0E .ae r oge n 16 19 20 19 14 22 13 20 14 19 19 20 22 0A.niger 15 22 17 19 23 16 20 21 16 19 0 0 0 23160

Studies on 4-ThiazolidinonesPART-VSECTION - II : BIOLOGICAL SCREENING STUDY OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL] -PIPERAZINE-1'-YL}-5-METHYL-4-THIAZOLIDINONE COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger10b-(22) 10b-(22) 10a-(21) 10b-(19)10b-(22)10e-(21) 10d-(23) 10d-(23) 10c-(20) 10e-(23)10f-(22) 10e-(20) 10e-(23) 10d-(19) 10h-(21)10h-(23) 10f-(22) 10g-(20) 10f-(22)10i-(22) 10h-(21) 10i-(22) 10h-(20)10j-(22)10j-(19)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23161

Studies on 4-ThiazolidinonesSECTION - IIISYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONES.4-Thiazolidinone derivatives represent one of the most active classes ofcompounds possessing a wide spectrum of biological activities, such as significant invitro activity against DNA and RNA viruses including polio viruses, hypnotic,sedative, analgesic, diuretic, antitubercular, anticonvulsant, antifungal, antibacterial,activity etc. These valid observations led us to synthesize some new 4-thiazolidinonederivatives. 2 - Aryl - 3 -N-{4'-[(4",4'''- difluorodiphenyl)- methyl]- piperazine-1'-yl}-5-carboxy methyl-4-thiazolidinones of Type (XI) have been synthesized by theheterocyclization of Schiff’s bases of 1 - N - arylideneamino - 4 -[(4', 4"-difluorodiphenyl)- methyl] -piperazines of Type (VII) with thiomalic acid.FRNNNSCOOHOFType-XI Type-XIR=Aryl R=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.162

Studies on 4-ThiazolidinonesIR SPECTRAL STUDY OF 2 -(4''''- METHOXYPHENYL)-3-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibretion-1Frequency in cmRef.Observed ReportedmodeC-H str.(asym.) 2910 2990-2850 474AlkaneC-H str. (sym.) 2857 2880-2860 "C-H def. (asym. 1454 1470-1430 "C-H def. (sym.) 1396 1395-1370 "Alkene -CH 2 str. 2522 2850-1790 "C-H str. 3085 3090-3030 "Aromatic C=C str 1496 1600-1450 "C-H i.p. (def.) 1161 1300-1100 "Halide C-F str. 759 800-600 475Piperazine C-N str. 1361 1360-1310 "Ether C-O-C str. 1197 1280-1200 "C-N str. 1080 1220-1020 "Thiazolidinone C=O str. 1705 1710-1650 "C-S-C str. 702 750-600 "Carboxylic acid O-H (brod) 3330 3400-3200 "163

Studies on 4-ThiazolidinonesNMR SPECTRAL STUDY OF 2 -(4''''-METHOXYPHENYL)-3-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONE.aH 3 COFjklmFj'k'il'm'bch hN N Nb'c'dSeh hO Hf'fHCOOHgInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.44-2.51 8H ddoublet C-H (h)2 2.61-2.64 1H triplet C-H (f)3 2.99-3.12 1H triplet C-H (f’)4 3.72 3H singlet Ar-OCH 3 (a)5 3.90-4.10 1H quartet Ar-H (e)6 5.06 1H singlet C-H (i)7 5.85 1H singlet Ar-H (d)8 6.95-6.99 2H doublet Ar-H (bb’)9 7.05-7.24 4H doublet Ar-H (jj’, mm’)10 7.27-7.29 2H doublet Ar-H (cc’)11 7.35-7.46 4H doublet Ar-H (kk’, ll’)12 11.10 1H singlet -COOH (g)164

Studies on 4-ThiazolidinonesMASS SPECTRAL STUDY OF 2-(4''''-METHOXYPHENYL)-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONE.165

Studies on 4-ThiazolidinonesMASS FRAGEMENT STUDY OF 2 - (4'''' - METHOXYPHENYL) - 3 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONE.F+oF+oFCC H 3OH 3 OCOOHFOCH 3+oNH 2H Nm/z = 137+oNm/z = 288FN H 2NNm/z = 303CFFm/z = 204+oH NOS+om/z = 267m/z = 108+oN H 2Fm/z = 219F+oFFFCH 3NH 3CFNH 3 OCOOHCH 3m/z = 110m/z = 275+oNm/z = 553NOSC H 3NHNNm/z = 317C+oFCFC H 3C H 3NH 3 OCOOHSNOm/z = 338+oHOOCSNNOO+oHNSCOOHm/z = 161+Fo +S oNN Nm/z = 447OCOOHH NCNNS+oNH 3 OCOOHNm/z = 517NOS+oH 3 OCOOHm/z = 245NHFm/z = 351O166

Studies on 4-ThiazolidinonesREACTION SCHEMEFNNHFFNaNO 20-5 0 C+ HClN N NOFFLiAlH 4N N NH 2FR-CHOCon.H 2 SO 4FFHSCH COOHRN N NH 2 CCOOHNNNSROHOOCFFType - XIR = Aryl167

Studies on 4-ThiazolidinonesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONES.[ A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4'''-methoxybenzylidene)-amino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-IV, Section-I (C), on page no-120[D]Synthesis of 2 -(4''''-methoxyphenyl)-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-carboxymethyl-4-thiazolidinone(11e):A mixture of 1- N -[(4'''- methoxybenzylidene)- amino]- 4 -[(4', 4"- difluorodiphenyl)-methyl]-piperazine (4.21gm, 0.01M) in benzene (25 ml) was taken, Deanstark apparatus was attached to it and thiomalic acid (1.50 gm, 0.01M) in benzenewas added slowly. Then it was refluxed for 15-16 hrs, during the course of thereaction the water was removed continuously. The benzene was distilled off to get thethiazolidinones. The solid product was filtered, dried and recrystallized from absolutealcohol. Yield: 84.50 %, M.P.137C.O 47. 56 %).N 3 F 2 S; Required: C: 62.92; H: 5.28; N: 7.59; Found : C:62.89; H: 5.25; N:(C 29 H 29dSimilarly, other 4-thiazolidinones were prepared. The physical constants arerecorde in Table No-11.[E]Biological Screening of 2 -aryl-3-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-5-carboxymethyl-4-thiazolidinones:Biological Screening were carried out as described in Part-I, Section-1 pageno-40. The zones of inhibition of test solution are recorded in Graphical Chart No-11.168

Studies on 4-ThiazolidinonesTABLE NO - 11 : PHYSICAL CONSTANTS OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE - 1' -YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.11a C 6 H 5 - C 28 H 27 O 3 N 3 F 2 S 523 114 67.42 8.03 8.0011b 2-OH-C 6 H 4 - C 28 H 27 O 4 N 3 F 2 S 539 127 74.63 7.79 7.7611c 4-OH-C 6 H 4 - C 28 H 27 O 4 N 3 F 2 S 539 148 68.10 7.79 7.7611d 2-OCH 3 -C 6 H 4 - C 29 H 29 O 4 N 3 F 2 S 553 175 74.00 7.59 7.5611e 4-OCH 3 -C 6 H 4 - C 29 H 29 O 4 N 3 F 2 S 553 137 84.50 7.59 7.5611f 2-Cl-C 6 H 4 - C 28 H 26 O 3 N 3 F 2 SCl 558 161 72.89 7.53 7.5011g 4-F-C 6 H 4 - C 28 H 26 O 3 N 3 F 3 S 541 192 69.71 7.76 7.7211h 2-NO 2 -C 6 H 4 - C 28 H 26 O 5 N 4 F 2 S 568 187 75.32 9.85 9.8111i 3-NO 2 -C 6 H 4 - C 28 H 26 O 5 N 4 F 2 S 568 153 72.87 9.85 9.8111j C 4 H 3 O - C 26 H 25 O 4 N 3 F 2 S 513 136 68.23 8.18 8.15169

Studies on 4-ThiazolidinonesGRAPHICAL CHART NO - 11 : BIOLOGICAL SCREENING OF 2 -ARYL-3-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL] -PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONES.30ZONE OF INHIBITION IN mm252015105011a 11b 11c 11d 11e 11f 11g 11h 11i 11j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 17 22 19 21 14 24 16 23 22 16 23 22 24 0B.cerus 16 22 19 21 16 22 17 23 20 13 22 23 21 0E .coli 20 17 23 16 15 22 20 16 15 22 21 21 23 0E .ae r oge n 16 19 12 20 13 22 14 18 16 19 19 20 22 0A.niger 17 19 22 14 23 21 18 22 21 20 0 0 0 23170

Studies on 4-ThiazolidinonesPART-VSECTION - III : BIOLOGICAL SCREENING STUDY OF 2 - ARYL - 3 - N -{4'-[(4", 4'''- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE-1'-YL}-5-CARBOXYMETHYL-4-THIAZOLIDINONES.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger11b-(22) 11b-(22) 11a-(20) 11b-(19)11c-(22)11d-(21) 11d-(21) 11c-(23) 11d-(20) 11e-(23)11f-(24) 11f-(22) 11f-(22) 11f-(22) 11f-(21)11h-(23) 11h-(23) 11g-(20) 11h-(18) 11h-(22)11i-(22) 11i-(20) 11j-(22) 11j-(19) 11i-(21)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23171

Studies on 2-AzetidinonesSTUDIES ON 2-AZETIDINONESINTRODUCTIONAzetidin-2-one, also called β-Lactam, is a four member cyclic amide whichwas first synthesized by Staudinger in 1907. 333 Because of the discovery of penicillinin 1928 by Fleming and its structural confirmation by X-ray crystallography, 334 thebioactivity of β-lactam compounds has been investigated intensively. 335 Before 1970,penicillin and cephalosporins were the antibiotics that attracted most synthetic effort.The four membered β-lactam (2-azetidinone) ring systems (I) has for many yearsbeen of great practical significance as the centre of reactivity of penicillins (II) andCephalosporin (III).CH 3CH3ROSHNOCOOKHNRNNHOOO( I ) ( II ) ( III )COOHH 3 COP. G. Summes 336 have been synthesized of simple β-lactams for testing asantibiotics, anti-depressants, sedatives etc. J. C. Sheeham et. al. 337 have been synthesisand extensively studied of 2-azitidinone derivatives. 2-azetidinone derivatives havebeen synthesis by different methods cited in literature. 338-347 A.J. Baxi et. al. 348 havebeen synthesized 2-azetidinone derivatives and also evaluted antimicrobialscreening.MECHANISMSynthesis of β-lactam of the addition of C - N and C = O component to forma ring substituted acetyl chloride with electron withdrawing substituents and atleastone hydrogen at α-carbon add to imines in the presence of amine bases. 349 The172

Studies on 2-Azetidinonesmechanism take place by non-concerted cycloaddition reaction as depicted in followingscheme (IV).( IV )The reaction may be experimented in many cases by treating a mixture of350,351the imine and dichloroacete acid with POCl 3 or POBr 3. It hasbeen observed that the acid chloride is formed as an intermediate through thephosphorus halide participate as an electrophillic catalyst as shown in following scheme(V).( V )Cyclo addition of diphenylketone to a performed imine 352 also formsβ-lactam.THERAPEUTIC IMPORTANCEβ-Lactam drugs are still the most widely described antibiotics in medicine. 3532-Azetidinone derivatives possess wide therapeutic activity viz. sedative,hypnotics, anticonvulsant, 354 herbicidal and antibacterial. 355 They are alsoeffective on the central nervous system. 356 A large number of 3-chloro monocyclic β-173

Studies on 2-Azetidinoneslactams have been prepared by cyclo addition of β,β-disubstituted enamines with arylisothiocyanates which possess a powerful antibacterial activity. 357J. Goto et. al. 358 have been synthesized a series of 7-β-(2-amino pyrimidinyl)-2-oxyimino acetamido-cephalosporins as useful antibiotics. Penicillins of type (VI)and there corresponding penicillins gave antibacterial activity.ORNHONSCH 3CH 3COONa( VI )Several alkyl, alkenyl, alkonyl, 2-azetidinones 359 and 3-alkyl-4-halomethyl/arylmethyl-2-azetidinones useful as intermediates for antibioties 360 have beenreported 4-(trifluoromethyl)-2-azetidinone derivatives 361,362 were prepared asintermediates for antibiotics.M. Sendai and co-workers 363 have prepared 2-azetidinones of type (VII) toprove the antibacterial activity of sulfazecins out of them when R =-CH 3 ,-CH 2 COOH and R 1 = -CONH 2 showed potent antibacterial activity comparableagainst Gram positive and Gram negative bacteria.N H 2NSONHNORR= -CH 3 , -CH 2 COOH( VII )R 1 = -CONH 2 , -CONHNH 2ONSO 3 HR 1174

Studies on 2-Azetidinones2 -Azetidinone derivatives have been reported as antiparkinson, antibacterialand antifungal, 364-371 antiinflammatory, 372-374 hypochloresterolimic 375and antimicrobial agents. 376V. Jayamma and co-workers 377 have prepared some new derivatives of 2-azetidinones and tested their antimicrobial activity. S. Giri et. al. 378 havesynthesized some 1-[5'-aryl-1',3',4'-thiadiazol-2'-yl]-3-chloro-4-substituted 2-azetidinones as potential fungicides.Morever, Saito et. al. 379 have synthesized some new 2-azetidinones as acarbapenem antibiotics. V. H. Shah et. al. 380 have reported 2-azetidinonesderivatives as antimicrobial and antitubercular agents. A. K. Khalafallah et.al. 381have assessed some new azetidinone derivatives for their antimicrobial activity. Severalco-workers have prepared some new 2-azetidinones and reported their antiinflammatoryactivity. 382R. H. Udupi et. al. 383 synthesized 2-azetidinones which shows goodantiinflammatory, antitubercular, bactericidal and fungicidal activity. Wayne D.Vaccaro and Co-workers 384 prepared some novel azetidinone derivatives ascholesterol absorption inhibitors, Brain A. Mckittrick and co-workers 385 haveprepared some new azetidinones display potent cholestorl absorption inhibitory activity.Ishwar K. Bhat et. al. 386 have been synthesized some 2-azetidinones asantibacterial and antifungal agent (VIII).ORClH 3 CONH C NCH 2 NHR=Substituted phenylO( VIII )K. H. Patel and A. G. Mehta 387 have been synthesized some novel 2-azetidinones as antibacterial activity (IX).175

Studies on 2-AzetidinonesRClNSNOR=Substituted phenyl ( IX )S. J. Wadher et. al. 388 have been synthesized some 2-azetidinones displaypotent as antibacterial and antifungal activity (X).RORClNSNClOOR= Substituted phenyl ( X )OS. Jubie et. al. 389 have been synthesized some 2-azetidinone derivatives showedpotent antibacterial activity comparable against Gram positive and Gram negativebacteria and antifungal activity (XI).RH 3 CONClR= Substituted phenyl ( XI )OSudhir Kumar Bhati and Ashok Kumar 390 have been synthesized some new 2-azetidinones evaluated for their anti-inflammatory, analgesic, ulcerogenic activities andtoxicity studies (XII).176

Studies on 2-AzetidinonesNNNHCH 2CNSNCNRNSOClR= Aryl ( XII )Ivan Plantan et. al. 391 have been synthesized as a stereoselective compounds of(1'S, 3R, 4R)-4-acetoxy-3-(2'-fluoro-1'-trimethylsilyloxyethyl)-2-azetidinone as a newfluorine-containing intermediate towards β-lactams is described (XIII).TMSOHOACFO( XIII )NH.Thus, in search of a more potential therapeutic agent by incorporatingazetidinone moiety in piperazine nucleus, it was contemplated to synthesis β-lactamof type (XII) by the condensation of chloro acetyl chloride with Schiff's bases inpresence of triethyl amine which has been described as under.SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYL-3-CHLORO-2-AZETIDINONES.177

Studies on 2-AzetidinonesSECTION - ISYNTHESIS AND BIOLOGICAL SCREENING OF 1 - N - {4' - [(4", 4''' -DIFLUORODIPHENYL) - METHYL] - PIPERAZINE -1'-YL} - 4 - ARYL - 3 -CHLORO - 2 - AZETIDINONES.2-Azetidinone derivatives represent one of the most active classes ofcompounds possessing a wide spectrum of biological activity such as powerfulantibiotic activity shown by monocyclic β-lactams, antidepressants, sedative,hypnotics, anticonvulsant, antiviral etc. In view of getting to synthesized 2-azetidinone derivatives of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-aryl-3-chloro-2-azetidinones of Type (XII) have been under taken by the chemoselective cyclization of Schiff's bases of 1-N-arylideneamino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines of Type (VII) with chloro acetyl chloride in thepresence of triethyl amine as a basic catalyst.FRNNNClOFType-XIIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.178

Studies on 2-AzetidinonesIR SPECTRAL STUDY OF 1 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) -METHYL]-PIPERAZINE-1'-YL}-4-(4''''-METHOXYPHENYL)-3-CHLORO-2-AZETIDINONE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibretion Frequency in cm -1 Ref.Observed ReportedmodeC-H str.(asym.) 2979 2990-2850 474AlkaneC-H str. (sym.) 2889 2880-2860 "C-H def. (asym. 1444 1470-1430 "C-H def. (sym.) 1371 1395-1370 "C-H str. 3051 3090-3030 "Aromatic C=C str 1568 1600-1450 "C-H i.p. (def.) 1282 1300-1100 "Halide C-F str. 773 800-600 475Piperazine C-N str. 1359 1360-1310 "Ether C-O-C str. 1265 1280-1200 "AzetidinoneC-N str. 1172 1220-1020 "C=O str. 1633 1710-1650 "Halide C-Cl str. 742 800-600 "179

Studies on 2-AzetidinonesNMR SPECTRAL STUDY OF 1 - N - {4' -[(4", 4'''- DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL} - 4 -(4''''-METHOXYPHENYL)-3-CHLORO-2-AZETIDINONE.OaCH 3Fijkli'hj'k'bcg fN N Ng'f'Odeb'c'Cll'FInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.49-2.55 4H doublet C-H (gg’)2 2.56-2.58 4H doublet C-H (ff’)3 3.71 3H singlet Ar-OCH 3 (a)4 4.89-4.91 1H doublet Ar-H (e)5 5.02 1H singlet C-H (h)6 5.34-5.37 1H doublet Ar-H (d)7 6.47-6.49 2H doublet Ar-H (bb')8 6.77-6.86 2H triplet Ar-H (ii’)9 6.90 2H singlet Ar-H (ll’)10 6.99-7.03 2H doublet Ar-H (jj’)11 7.26-7.28 2H doublet Ar-H (kk’)12 7.29-7.33 2H doublet Ar-H (cc’)180

Studies on 2-AzetidinonesMASS SPECTRAL STUDY OF 1-N- {4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE -1'-YL} - 4 -(4''''-METHOXYPHENYL)-3-CHLORO-2-AZETIDINONE.181

Studies on 2-AzetidinonesMASS FRAGEMENT STUDY OF 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-(4''''-METHOXYPHENYL)-3-CHLORO-2-AZETIDINONE.OCH 3NH 2+om/z = 137FFm/z = 96+oFFNm/z = 288+oNHFFFOCH 3+o +oN N N H 2m/z = 303Om/z = 206CH 3NNHOm/z = 108CH 3+oH NOCH 3Om/z = 211+oClN H 2Fm/z = 219+oFFCH 3NH 3+oNNm/z = 497NOClH 3 CNHNNm/z = 317+oCm/z = 275H Nm/z = 86C H 3NNHm/z = 100+oF+oNHFm/z = 204OFCH 3+o+o +oH NClFNN+oNClNFNNON+oCH 3+oClNHm/z = 194FFH 3 CCH 3NNm/z = 282OClOm/z = 105Fm/z = 391 m/zO= 403FO182

Studies on 2-AzetidinonesREACTION SCHEMEFNNHFFNaNO 20-5 0 C+ HClN N NOFFLiAlH 4N N NH 2FR-CHOCon.H 2 SO 4FFRN N NClCOCH 2 ClREt 3 NNNNOClFFType - XIIR = Aryl183

Studies on 2-AzetidinonesEXPERIMENTALSSYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYL-3-CHLORO- 2 -AZETIDINONES.[A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 1-N-[(4'''-methoxybenzylidene)-amino]-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-IV, Section-I (C), on page no-120[D] Synthesis of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-(4''''-methoxyphenyl)-3-chloro-2-azetidinone(12e):A mixture of 1 - N -[(4'''- methoxybenzylidene)- amino]- 4 -[(4', 4"- difluorodiphenyl)-methyl]- piperazine (4.21gm, 0.01M) in dry dioxane (25 ml) was added to awell stirred mixture of chloacetylchloride (1.90 ml, 0.02M) and triethylamine (3.35ml, 0.024M) in dry dioxane at 0°C. The reaction mixture was then stirred for 10-15hrs and kept for 2 days at room temperature. The reaction mixture was then pouredinto crushed ice, filtered and washed with water. The solid product was dried and recrystallizedfrom ethanol and water. Yield: 74.60 %, M.P.135 o C.(C 27 H 26 O 2 N 3 F 2 Cl; Required: C: 65.12; H: 5.26; N: 8.44; Found : C:65.10; H: 5.23; N:8.41 %).Similarly, other 2-azetidinones were prepared. The physical constants arerecorded in Table No-12.[E] Biological Screening of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-aryl-3-chloro-2-azetidinones:Biological Screening were carried out as described in Part-I, Section-1 pageno-40. The zones of inhibition of test solution are recorded in Graphical Chart No-12.184

Studies on 2-AzetidinonesTABLE NO - 12 : PHYSICAL CONSTANTS OF 1 - N -{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL} - 4 -ARYL-3-CHLORO- 2 -AZETIDINONES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.12a C 6 H 5 - C 26 H 24 ON 3 F 2 Cl 467 202 68.17 8.98 8.9512b 2-OH-C 6 H 4 - C 26 H 24 O 2 N 3 F 2 Cl 483 163 70.24 8.68 8.6612c 4-OH-C 6 H 4 - C 26 H 24 O 2 N 3 F 2 Cl 483 147 63.72 8.68 8.6612d 2-OCH 3 -C 6 H 4 - C 27 H 26 O 2 N 3 F 2 Cl 497 159 64.65 8.44 8.4112e 4-OCH 3 -C 6 H 4 - C 27 H 26 O 2 N 3 F 2 Cl 497 135 74.60 8.44 8.4112f 2-Cl-C 6 H 4 - C 26 H 23 ON 3 F 2 Cl 2 502 178 73.42 8.36 8.3212g 4-F-C 6 H 4 - C 26 H 23 ON 3 F 3 Cl 485 149 67.38 8.65 8.6212h 2-NO 2 -C 6 H 4 - C 26 H 23 O 3 N 4 F 2 Cl 512 127 76.54 10.92 10.9012i 3-NO 2 -C 6 H 4 - C 26 H 23 O 3 N 4 F 2 Cl 512 187 69.60 10.92 10.9012j C 4 H 3 O - C 24 H 22 O 2 N 3 F 2 Cl 457 169 70.00 9.18 9.15185

Studies on 2-AzetidinonesGRAPHICAL CHART NO - 12 : BIOLOGICAL SCREENING OF 1 - N - {4'- [(4", 4'''- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE-1'-YL}-4-ARYL-3-CHLORO-2-AZETIDINONES.30ZONE OF INHIBITION IN mm252015105012a 12b 12c 12d 12e 12f 12g 12h 12i 12j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 21 14 22 17 23 12 19 24 21 20 23 22 24 0B.cerus 14 22 19 23 15 20 16 13 21 22 22 23 21 0E .coli 18 21 17 20 13 23 16 19 20 22 21 21 23 0E .aerogen 20 15 18 20 16 21 14 22 15 19 19 20 22 0A.niger 17 22 20 19 20 16 23 21 19 22 0 0 0 23186

PART-VIStudies on 2-AzetidinonesSECTION - I : BIOLOGICAL SCREENING STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYL-3-CHLORO-2-AZETIDINONES COMPARE WITH KNOWN STANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger12a-(21) 12b-(22) 12b-(21) 12a-(20)12b-(22)12c-(22) 12d-(23) 12d-(20) 12c-(18) 12g-(23)12e-(23) 12f-(20) 12f-(23) 12d-(20) 12h-(21)12h-(24) 12i-(21) 12i-(20) 12f-(21) 12j-(22)12i-(21) 12j-(22) 12j-(22) 12h-(22)12j-(20) 12j-(19)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23187

STUDIES ON 5-OXO-IMIDAZOLINESStudies on 5-Oxo-ImidazolinesINTRODUCTIONThe five membered heterocyclic ring system 5-oxo-imidazolines have twonitrogen atom at 1- and 3-positions and a carbonyl group at 5-position.OHNN(I)The discovery of the 2-substituted-5-imidazolines dates back to the year 1888,when A. W. Hoffman 392 for the first time discovered 5-oxo-imidazoline by heating N-diacetylethylene diamine in a stream of dry hydrogen chloride. Moreover, somecompounds were prepared by A. Ladenburg 393 by the fusion of two equivalents ofsodium acetate with one equivalent of ethylene diamine dihydrochloride.SYNTHETIC ASPECTVarious methods have been reported for the synthesis of imidazolinones inLiterature. 394 Aminolysis of oxazolone with amine leads to the formation ofimidazolinones which has been reported in literature. 3951. Feng-Jun-Cai et. al. 396 have been synthesized 5-imidazolinone derivatives bymicro-waves irradiation.2. A. Saxena et. al. 397 have been synthesized new imidazolinones.NON Ar -OClONH 2NHAr -ONONNHCl3. H. A. Allimony et. al. 398 have been synthesized new imidazolinonederivatives by conventional method.188

Studies on 5-Oxo-ImidazolinesMECHANISMIn present study aromatic aldehyde were condensed with benzoyl glycine inpresence of anhydrous sodium acetate and acetic anhydride to get azlactones /oxazolinones. 399OORR-CHO+HNOHONOHOH(CH 3 CO) 2 OCH 3 COONaNOOR'R'R'R = ArylR' = -C 6 H 5 , -4-OCH 3 -C 6 H 4Azalactone reacts with variety of compounds such as water, alcohols, aminesand hydrogen halides. Amides of α-acylamino acryclic acids obtained from thecondensation of azalactone and primary amine can be converted to imidazolinones asshown in reaction.RRROONHNNRO1 NH 2HNR 1O POCl3 NXXX(a) (b) (c)R 1OR' -NH 2 ,Dry C 5 H 5 N / Abs.C 2 H 5 OH,K 2 CO 3The ring closer can be effected under a variety of conditions. Substitutedanilides have been converted to imidazolinone derivatives by the action of POCl 3 . Inorder of get variety of useful pharmacological important compounds, reaction ofazalactones have been extensively investigated with different type of compounds suchas aromatic amines, 400,401 hydrazine hydrate, 402 aromatic amino acids, phenylhyrdazine 403 and ammonia.189

Studies on 5-Oxo-ImidazolinesTHERAPEUTIC IMPORTANCENaphazoline hydrochloride, xylometazoline hydrochloride etc. are variousimidazolinone derivatives which have been used as adrenergic stimulants andtolazoline and phenotolamine as adrenergic blocking agents. Various imidazolinonesare known to exhibit a broad spectrum of biological activities such as,1. Antitubercular 4042. Potent CNS depressant 405,4063. Insecticidal 4074. Antiviral 4085. Hypertensive 4096. Antiinflammatory 410-4127. Glucagon antagonists 4138. Antimicrobial 4149. Thrombin inhibitor 41510. Anticonvulsant 416,41711. Sedative and hypnotics 41812. Bactericidal 419,42013. Fungicidal 421,42214. Antiparkinson 423,42415. Anthelmintic 42516. Antihistaminic 42617. Anticancer 427,42818. Antidiabatic 429F. C. Geoffrey et. al 430 and B. L. Pilkington et. al. 431 have been synthesizedand studied antifungal activity of imidazolinones. L. J. Peter and Co-worker 432 havebeen prepared substituted imidazolinones which inhibited the abnormal cell growth inhuman body. S. Lauter and Co-worker 433 have been isolated imidazoline fromdifferent methods and tested for the treatment of cytokine release. Imidazolinederivatives have been prepared by D. Erick and co-worker 434 showing anti-HIVactivity. Ding Ming-Wu et. al. 435 have been prepared new imidazolines andreported their antifungal activity.V. Kolhe et. al. 436 has reported anti-AIDS, antibacterial and fungicidal activityof 5-oxo-imidazolines. B. R. Shah and co-worker 437 have been prepared some newimidazolines and reported anticancer and anti HIV activity.190

Studies on 5-Oxo-ImidazolinesV. Akyoshi et. al. 438 have been prepared some new imidazolinone derivatives(II) and reported their herbicidal activity. Agrochemical activity of imidazolinoneshas been reported by J. P. Bascou and co-workers. 439R. Sharma and co-workers 440 have been reported antimicrobial activity of 5-oxo-imidazolines (III).R 3NC H 3NNHOHNCH 3CH 3NONNHN( II )O CH 3R 1NRN2 ( III )K. K. Awasthi et. al. 441 (IV) have been synthesized some new imidazolinonederivatives and reported their antimicrobial activity.ROSH 3 CNNNHNHCH 3( IV )CONTRIBUTION FROM OUR LABORATORYA. R. Parikh et. al. 442 have been synthesized imidazolinones bearing thiazoleas moderately active bactericidal and fungicidal. H. H. Parekh et. al. 443 haveelaborated better activity for some imidazolinones with activated benzylidene group at5-position.D. M. Purohit et. al. 444 have been synthesized 5-oxo-imidazoline (V)derivatives in “Fluchloralin” moiety. D. M. Purohit et. al. 445,446 have been synthesized191

Studies on 5-Oxo-Imidazolines5-oxo-imidazolines (VI) in “dichlorine” nucleus. D. M. Purohit et. al. 447 have beensynthesized 5-oxo-imidazolines (VII) in 2, 4-Dichloro derivatives.NO 2ORClORF 3 CNHNNO 2 NNNO 2 NNO 2 CH 3ClCl( V )ClOHN OSON( VI )NOCH 3NNRRNNOOSO( VI )OCH 2 COOHClCl( VII )V. N. Patoliya et. al. 448,449 have been synthesized 5-oxo-imidazolines (VIII,IX)evaluated its antimicrobial activity.ONORNNNONNH 3 CCH 3NONRCl( VIII ) ( IX )A. R. Parikh et. al. have been synthesized imidazolinones bearingphthalazine, 450 2-base of chloramphenicol 451 moiety at one position which wereevaluated for their antimicrobial activity. A. R. Parikh et. al. 452 have been reported 4-192

Studies on 5-Oxo-Imidazolines(4'-Arylidine-2'- phenyl-5'-oxo-imidazolin-1-yl) benzophenones which were screenedfor their antimicrobial activity. Biplab De et. al. 453 have been reported some new 5-oxoimidazoline as antimicrobial agents. Imidazolinones have been reported to possessantioxidant activity.Moreover, A. R. Parikh, H. H. Parekh and co-workers have been synthesizedthe newer 5-oxo-imidazolines with different variety of activities described as under.1) 1-p-(4'-Acetamidobenzenesulphonamido) phenyl-2-phenyl-4 -substitutedbenzal-5-oxoimidazolines. 4542) Synthesis of biologically active 5-oxo-imidazolines. 455-4573) Preparation and antimicrobial activity of 1-N-Aryl-2-methyl-4'-(8-hydroxyquinolin-7'-yl)-methine-5-oxoimidazolines. 4584) Synthesis of some 5-imidazolinones as novel bioactive compounds derived frombenzimidazole. 4595) Synthesis and biological screening of 2-Chloro-8-methylquinolin-3-yl-N-(2'-phenyl-4'-arylidine-5'-oxo-imidazolin-1'-yl)-azomethines. 460Moreover, Yoneda Naoto et. al. 461 have been synthesized imidazolinones asantihypertensive agent. R. C. Dage et. al. 462 have been synthesized cardiotonicimidazolones. Armando Rossello et. al. 463 have been synthesized imidazolones asantifungal agent. A. B. Cooper and co-workers 464 have been found that imidazolonesare inhibitors of farnesyl protein transferase. Machii Daisuke et. al. 465 have beensynthesized new imidazolones as a telomerase inhibitors and antitumor agents M. R.Jean et. al. 466 have been synthesized imidazolones and tested as antileishmanial agent.Chafiq Hamdouchi et. al. 467 have been synthesized imidazolinones and screened fortheir potent and broad spectrum activity. M. L. Irene et. al. 468 have been synthesizedimidazolinones and tested as antiretroviral activity. Xu Zhi-Feng et. al. 469 have beensynthesized imidazolinones as biological agent.Tarik El-Sayed Ali et. al. 470 have been synthesized some new imidazolinonederivatives and reported their antifungal activity (X).193

Studies on 5-Oxo-ImidazolinesOArONNClNOAr = Substituted Phenyl ( X )N. C. Desai et. al. 471 have been synthesized some new 5-imidazolinonederivatives and reported their antibacterial and antifungal activity.Murlidhar P. Wadekar et. al. 472 have been synthesized some novel 5-oxoimidazolinescontaining azo linkages and reported their antimicrobial activity againstgram positive and gram negative(XI).OArRNNNNNOHR= -Cl, -Br, -CH 3 , -OCH 3Ar = Substituted Phenyl( XI )With a view to getting better therapeutic agent, it was contemplated tosynthesized 5-imidazolinones to enhance the overall activity of resulting compoundswhich have been described as under.194

Studies on 5-Oxo-ImidazolinesSECTION - I : SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYLIDENE-2-PHENYL-5-OXO-IMIDAZOLINES.SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING OF 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYLIDENE-2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINES.195

Studies on 5-Oxo-ImidazolinesSECTION:-ISYNTHESIS AND BIOLOGICAL SCREENING 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYLIDENE-2-PHENYL-5-OXO-IMIDAZOLINES.5-Imidazolinones represent one of the most active classes of compoundshaving a wide spectrum of biological activities with an aim to getting bettertherapeutic agent like anticonvulsant, potent CNS depressant, anti-inflammatory,antimicrobial, anticancer, sedative, hypnotics and mono amino oxidase (MOA)inhibitors etc. In view of getting to synthesized 5-oxo-imidazoline derivatives of 1-N-{4'-[(4",4'''-difluorodiphenyl)- methyl]- piperazine -1'-yl}-4- arylidene-2-phenyl -5-oxo-imidazolines of Type (XIII) have been under taken by the condensation of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine with different oxazolones.FONNNNRFType-XIIIR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.196

Studies on 5-Oxo-ImidazolinesIR SPECTRAL STUDY OF 1 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) -METHYL] - PIPERAZINE - 1' - YL} - 4 - (4""- METHOXYBENZYLIDENE) -2-PHENYL-5-OXO-IMIDAZOLINE.Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibretion Frequency in cm -1 Ref.mode Observed ReportedC-H str.(asym.) 2937 2990-2850 474AlkaneC-H str. (sym.) 2875 2880-2860 "C-H def. (asym.) 1443 1470-1435 "C-H def. (sym.) 1374 1390-1370 "C-H str. 3090 3090-3030 "Aromatic C=C str 1523 1600-1450 "C-H i.p. (def.) 1197 1300-1100 "Halide C-F str. 785 800-600 475Piperazine C-N str. 1323 1360-1310 "Ether C-O-C str. 1274 1280-1200 "C-N str. 1172 1220-1020 "Imidazoline C=N str. 1575 1612-1593 "C=O str. 1687 1710-1650 "197

Studies on 5-Oxo-ImidazolinesNMR SPECTRAL STUDY OF 1 - N - {4'-[(4", 4'''- DIFLUORODIPHENYL) -METHYL] - PIPERAZINE - 1' - YL} - 4 - (4""- METHOXYBENZYLIDENE) -2 -PHENYL-5-OXO-IMIDAZOLINE.aO CH 3Fj'bb'jklmFk'hiNh'l'm'gNg'efcONNe'dc'ffInternal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.43-2.44 8H doublet C-H (gg’, hh’)2 3.75 3H singlet Ar-OCH 3 (a)3 5.10 1H singlet C-H (i)4 7.28-7.30 2H doublet Ar-H (bb’)5 7.42-7.49 4H ddoublet Ar-H (jj’, mm’)6 7.61-7.64 2H doublet Ar-H (cc’)7 7.71-7.74 4H doublet Ar-H (kk’, ll’)8 7.81-7.84 3H doublet Ar-H (f)9 7.95-8.10 3H doubletAr-H (ee’)C-H (d)198

Studies on 5-Oxo-ImidazolinesMASS SPECTRAL STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-(4""-METHOXYBENZYLIDENE) -2-PHENYL-5-OXO-IMIDAZOLINE.199

Studies on 5-Oxo-ImidazolinesMASS FRAGEMENT STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-(4""-METHOXYBENZYLIDENE) -2-PHENYL-5-OXO-IMIDAZOLINE.Fm/z = 204+oFF+oNm/z = 288NHFF+oN N N H 2m/z = 303OCH 3+OoH NNm/z = 108 m/z = 84CH 3H 2 CON +oO+oNNNHm/z = 180OH NN+om/z = 202H N+oNm/z = 256ONNN H 2CH 2F+om/z = 219m/z = 78F+o+oFOCH 3F+oFm/z = 96FCH 3NH 3CF+om/z = 275FFNm/z = 564NONNOH NNNm/z = 331OOCH 3+oFH NNHm/z = 86OH Nm/z = 160+oN+oNm/z = 194NHF+oFFNNm/z = 458+oNONCH 2FFNNm/z = 488NONOCH 3H 3CCH 3+oNH NOONNm/z = 349CH 3+oNNNm/z = 362200

REACTION SCHEMEStudies on 5-Oxo-ImidazolinesFNNHFFNaNO 2 + HCl0-5 0 CN N NOFFLiAlH 4N N NH 2RFPyridineNFOOONNNNRFType - XIIIR = Aryl201

[A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 4-(4'-methoxybenzylidene)-2-phenyl-5-oxazolone.A mixture of (benzoylamino)-acetic acid, (hippuric acid) (5.19gm, 0.029M),acetic anhydride (3.26gm, 0.032M), sodium acetate (2.62gm, 0.032M) and 4-methoxybenzaldehyde (4.35gm, 0.032 mol) was heated on a water bath for 4 hrs. Resultingmass poured into ice cold water, filtered and crystallized from acetone and water.Yield: 86%, M.P. 155 o C.Similarly, other oxazolones have been prepared by Erlen Meyer method. 473[D] Synthesis of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}- 4-(4""-methoxybenzylidene)-2-phenyl-5-oxo-imidazolines(13e):A mixture of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine (3.03gm,0.01M) and 4-(4'-methoxybenzylidene)-2-phenyl-5-oxazolone (2.79 gm, 0.01 M) indry pyridine (20 ml) was refluxed for 12 hrs. in oil bath. Resulting mass was pouredinto crushed ice and neutralized with dil. HCl, filtered and the product wasrecrystallized from 1,4-dioxan.Yield: 65.85%, M.P.142 o C. (C 34 H 30 O 2 N 4 F 2 ; Required: C: 72.32; H: 5.36; N: 9.92; Found : C: 72.30; H: 5.34; N: 9.90 %).Similarly, other 5-oxo-imidazolines have been prepared. The physicalconstants are recorded in Table No.13.Studies on 5-Oxo-ImidazolinesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYLIDENE-2-PHENYL-5-OXO-IMIDAZOLINES.[E] Biological Screening of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-arylidene-2-phenyl-5-oxo-imidazolines.Biological Screening was carried out as described in Part-I, Section-I, Pageno-40.The zone of inhibition of the test solution are recorded in Graphical Chart No-13.202

Studies on 5-Oxo-ImidazolinesTABLE NO - 13 : PHYSICAL CONSTANTS OF 1 - N - {4'-[(4", 4'''- DIFLUORODIPHENYL)- METHYL]- PIPERAZINE -1'-YL} -4 - ARYLIDENE-2-PHENYL-5-OXO-IMIDAZOLINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.13a C 6 H 5 - C 33 H 28 ON 4 F 2 534 134 65.00 10.48 10.4513b 2-OH-C 6 H 4 - C 33 H 28 O 2 N 4 F 2 550 114 67.54 10.18 10.1513c 4-OH-C 6 H 4 - C 33 H 28 O 2 N 4 F 2 550 104 72.32 10.18 10.1513d 2-OCH 3 -C 6 H 4 - C 34 H 30 O 2 N 4 F 2 564 137 75.51 9.92 9.9013e 4-OCH 3 -C 6 H 4 - C 34 H 30 O 2 N 4 F 2 564 142 65.85 9.92 9.9013f 2-Cl-C 6 H 4 - C 33 H 27 ON 4 F 2 Cl 569 162 69.24 9.85 9.8313g 4-F-C 6 H 4 - C 33 H 27 ON 4 F 3 552 113 63.25 10.14 10.1213h 2-NO 2 -C 6 H 4 - C 33 H 27 O 3 N 5 F 2 579 154 59.63 12.08 12.0513i 3-NO 2 -C 6 H 4 - C 33 H 27 O 3 N 5 F 2 579 140 57.87 12.08 12.0513j C 4 H 3 O - C 31 H 26 O 2 N 4 F 2 524 127 69.70 10.68 10.65203

Studies on 5-Oxo-ImidazolinesGRAPHICAL CHART NO - 13 : BIOLOGICAL SCREENING OF 1 - N - {4'-[(4", 4'''- DIFLUORODIPHENYL) - METHYL] -PIPERAZINE-1'-YL}-4-ARYLIDENE-2-PHENYL-5-OXO-IMIDAZOLINES.30ZONE OF INHIBITION IN mm252015105013a 13b 13c 13d 13e 13f 13g 13h 13i 13j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 22 15 19 21 17 24 18 16 21 22 23 22 24 0B.cerus 16 21 15 22 14 20 19 23 13 21 22 23 21 0E .coli 14 20 14 21 15 22 15 19 23 19 21 21 23 0E .aerogen 18 16 22 14 16 20 17 19 22 18 19 20 22 0A.niger 19 22 19 21 16 20 14 23 17 23 0 0 0 23204

Studies on 5-Oxo-ImidazolinesPART-VIISECTION - I : BIOLOGICAL SCREENING STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-ARYLIDENE-2-PHENYL-5-OXO-IMIDAZOLINES COMPARE WITH KNOWN STANDARD DRUGS .Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger13a-(22) 13b-(21) 13b-(20) 13a-(18) 13b-(22)13d-(21) 13d-(22) 13d-(21) 13c-(22) 13d-(21)13f-(24) 13f-(20) 13f-(22) 13f-(20) 13h-(23)13i-(21) 13h-(23) 13i-(23) 13h-(19) 13j-(23)13j-(22) 13j-(21) 13i-(22)13j-(18)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23205

Studies on 5-Oxo-ImidazolinesSECTION:-IISYNTHESIS AND BIOLOGICAL SCREENING 1-N-{4'-[(4",4'''-DIFLUORODIPHENYL)-METHYL] - PIPERAZINE - 1' -YL} - 4 - ARYLIDENE - 2 - (4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINES.5-Imidazolinones represent one of the most active classes of compoundshaving a wide spectrum of biological activities with an aim to getting bettertherapeutic agent like anticonvulsant, potent CNS depressant, anti-inflammatory,antimicrobial, anticancer, sedative, hypnotics and mono amino oxidase (MOA)inhibitors etc. In view of getting to synthesized 5-oxo-imidazoline derivatives of 1-N-{4'-[(4", 4'''-difluorodiphenyl)- methyl]- piperazine-1'-yl}-4-arylidene-2-(4""-methoxyphenyl)-5-oxo-imidazolines of Type(XIV) have been under taken by the condensationof 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine with different oxazolones.FONNNNRFType-XIVC H 3OR=ArylThe constitution of the synthesized compounds have been characterized byusing elemental analysis, IR, 1 H Nuclear Magnetic Resonance spectroscopy andfurther supported by mass spectroscopy and TLC.All the products have been screened for their in vitro biological assay likeantibacterial activity towards Gram positive and Gram negative bacterial strains andantifungal activity towards Aspergillus niger at a concentration of 50 µg/ml. Thebiological activities of the synthesized compounds were compared with standarddrugs. The details have been cited in part-I, section-I, page no-42, Table no. A.206

Studies on 5-Oxo-ImidazolinesIR SPECTRAL STUDY OF 1 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) -METHYL] - PIPERAZINE - 1' - YL} - 4 - (4""'- METHOXYBENZYLIDENE) -2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINE.FONNNNOCH 3FC H 3OInstrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:4000-400 cm -1 (KBr disc).Type Vibretion Frequency in cm -1 Ref.mode Observed ReportedC-H str.(asym.) 2937 2990-2850 474AlkaneC-H str. (sym.) 2866 2880-2860 "C-H def. (asym.) 1469 1470-1435 "C-H def. (sym.) 1377 1390-1370 "C-H str. 3055 3090-3030 "Aromatic C=C str 1579 1600-1450 475C-H i.p. (def.) 1259 1300-1100 "Halide C-F str. 761 800-600 "Piperazine C-N str. 1311 1360-1310 "Ether C-O-C str. 1228 1280-1200 "C-N str. 1099 1220-1020 "Imidazoline C=N str. 1608 1612-1593 "C=O str. 1633 1710-1650 "207

Studies on 5-Oxo-ImidazolinesNMR SPECTRAL STUDY OF 1 - N - {4' - [(4", 4'''- DIFLUORODIPHENYL) -METHYL] - PIPERAZINE - 1' -YL} - 4 - (4""'- METHOXYBENZYLIDENE) -2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINE.Fj'aH 3 CbOb'jklmFk'cOh gi N N NNh' g'l'em'fe'dc'aH 3 COf'Internal Standard: TMS; Solvent: CDCl 3 ; Instrument: BRUKER Spectrometer(300MHz)SignalNo.Signal Position(δppm)Relative No.of protonsMultiplicityInference1 2.50-2.51 8H doublet C-H (gg’, hh’)2 3.73 6H singlet Ar-OCH 3 (a)3 5.20 1H singlet C-H (i)4 6.68-6.70 2H doublet Ar-H (bb’)5 6.91-6.99 2H doublet Ar-H (ff’)6 7.27-7.34 4H triplet Ar-H (jj’, mm’)7 7.55-7.59 4H triplet Ar-H (kk’, ll’)8 7.66-7.73 2H doublet Ar-H (cc’)9 7.89-7.93 2H doublet Ar-H (ee’)10 8.47 1H singlet C-H (d)208

Studies on 5-Oxo-ImidazolinesMASS SPECTRAL STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-(4""'-METHOXYBENZYLIDENE) -2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINE.209

Studies on 5-Oxo-ImidazolinesMASS FRAGEMENT STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4-(4""'-METHOXYBENZYLIDENE) -2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINE.H 3 COH NFFm/z = 86+om/z = 96NH+o+om/z = 108FF+oNm/z = 288FNHF+oN N N H 2m/z = 303FFFm/z = 204+oH NONm/z = 202OO+oCH 3CH 3OC H 2NNNHm/z = 180N+oH NNm/z = 286H CO3NONCH 2FH 2 Nm/z = 219+o+oFFOC H 3CH 3NH 3C H 3OC H 3CNm/z = 275NNOFF+oFO CH 3m/z = 379N+om/z = 476C H 3+oNONONFFFNm/z = 488Nm/z = 594C H 3O+oN NNONNCH 2FNNm/z = 500NNON+oOCH 3H NOC H 3H NONNF+oNONm/z = 331NNOm/z = 392m/z = 194CH 3NH+oF+oC H 3OC H 3O210

REACTION SCHEMEStudies on 5-Oxo-ImidazolinesFNNHFFNaNO 20-5 0 C+ HClN N NOFFLiAlH 4N N NH 2RFPyridineFONOOCH 3ONNNNRFType - XIVH C3OR = Aryl211

Studies on 5-Oxo-ImidazolinesEXPERIMENTALSYNTHESIS AND BIOLOGICAL SCREENING 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL] - PIPERAZINE - 1'-YL} - 4 - ARYLIDENE - 2 - (4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINES.[A] Synthesis of 1-nitroso-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (A), on page no-52[B] Synthesis of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine:See, Part-I, Section-II (B), on page no-52[C] Synthesis of 4 - (4''-methoxybenzylidene) - 2 - (4'-methoxyphenyl) -5 -oxazolone.A mixture of [(4-methoxybenzoyl)amino]-acetic acid (6.06gm, 0.029M),acetic anhydride (3.26gm, 0.032M), sodium acetate(2.62gm, 0.032M) and 4-methoxybenzaldehyde (4.35gm, 0.032 mol) was heated on a water bath for 4 hrs. Resultingmass poured into ice cold water, filtered and crystallized from acetone and water.Yield: 82%, M.P. 185 o C.Similarly, other oxazolones have been prepared by Erlen Meyer method. 473[D] Synthesis of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine-1'-yl} - 4 -(4""'-methoxybenzylidene) - 2 - (4""-methoxyphenyl) - 5 - oxo -imidazolines(14e):A mixture of 1-amino-4-[(4',4"-difluorodiphenyl)-methyl]-piperazine (3.03gm,0.01M) and 4-(4''-methoxybenzylidene)-2-(4'-methoxyphenyl)-5-oxazolone (3.09 gm,0.01 M) in dry pyridine (20 ml) was refluxed for 12 hrs. in oil bath. Resulting masswas poured into crushed ice and neutralized with dil. HCl, filtered and the productwas recrystallized from 1,4-dioxan.Yield: 69.52 %, M.P.117 o C. (C 35 H 32 O 3 N 4 F 2 ;Required : C: 70.69; H: 5.42; N: 9.42; Found : C: 70.67; H: 5.39; N: 9.40 %).Similarly, other 5-oxo-imidazolines have been prepared. The physicalconstants are recorded in Table No.14.[E] Biological Screening of 1-N-{4'-[(4",4'''-difluorodiphenyl)-methyl]-piperazine -1'- yl} - 4 - arylidene - 2 - (4""-methoxyphenyl) - 5 - oxo -imidazolines.Biological Screening was carried out as described in Part-I, Section-I, Pageno-40.The zone of inhibition of the test solution are recorded in Graphical Chart No-14.212

Studies on 5-Oxo-ImidazolinesTABLE NO - 14 : PHYSICAL CONSTANTS OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)-METHYL]-PIPERAZINE-1'-YL}-4 -ARYLIDENE-2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINES.Sr. No. R Molecular Formula M.W.M.P.0 CYield%Calcd.%of NitrogenFound.14a C 6 H 5 - C 34 H 30 O 2 N 4 F 2 564 164 64.22 9.92 9.9014b 2-OH-C 6 H 4 - C 34 H 30 O 3 N 4 F 2 580 127 66.37 9.65 9.6214c 4-OH-C 6 H 4 - C 34 H 30 O 3 N 4 F 2 580 130 71.42 9.65 9.6214d 2-OCH 3 -C 6 H 4 - C 35 H 32 O 3 N 4 F 2 594 152 70.65 9.42 9.4014e 4-OCH 3 -C 6 H 4 - C 35 H 32 O 3 N 4 F 2 594 117 69.52 9.42 9.4014f 2-Cl-C 6 H 4 - C 34 H 29 O 2 N 4 F 2 Cl 599 154 64.43 9.35 9.3214g 4-F-C 6 H 4 - C 34 H 29 O 2 N 4 F 3 582 172 65.75 9.62 9.6014h 2-NO 2 -C 6 H 4 - C 34 H 29 O 4 N 5 F 2 609 168 59.00 11.49 11.4614i 3-NO 2 -C 6 H 4 - C 34 H 29 O 4 N 5 F 2 609 145 60.45 11.49 11.4614j C 4 H 3 O - C 32 H 28 O 3 N 4 F 2 554 135 68.71 10.10 10.08213

Studies on 5-Oxo-ImidazolinesGRAPHICAL CHART NO - 14 : BIOLOGICAL SCREENING OF 1 - N -{4'-[(4", 4'''- DIFLUORODIPHENYL)- METHYL] -PIPERAZINE-1'-YL}-4-ARYLIDENE-2-(4""-METHOXYPHENYL)-5-OXO-IMIDAZOLINES.30ZONE OF INHIBITION IN mm252015105014a 14b 14c 14d 14e 14f 14g 14h 14i 14j Ampicillin ChloramphenicolNorfloxacinGreseofulvinB.subtillis 16 22 13 20 19 21 17 24 23 14 23 22 24 0B.cerus 19 16 20 17 22 15 23 15 16 22 22 23 21 0E .coli 14 22 18 20 16 23 20 17 22 20 21 21 23 0E .aerogen 22 18 16 16 20 14 22 15 21 17 19 20 22 0A.niger 18 21 15 22 18 16 23 14 21 17 0 0 0 23214

Studies on 5-Oxo-ImidazolinesPART-VIISECTION - II : BIOLOGICAL SCREENING STUDY OF 1-N-{4'-[(4", 4'''-DIFLUORODIPHENYL)- METHYL]- PIPERAZINE-1'-YL} - 4 - ARYLIDENE- 2 - (4""- METHOXYPHENYL)- 5 - OXO - IMIDAZOLINES COMPARE WITH KNOWNSTANDARD DRUGS.Antibacterial activity Antifungal activityZone of inhibition in m. m. Zone of inhibition in m. m.Drugs B. subtillis B. cerus E. coli E. aerogen A. niger14b-(22) 14c-(20) 14b-(22) 14a-(22)14b-(21)14d-(20) 14e-(22) 14d-(20) 14b-(18) 14d-(22)14f-(21) 14g-(23) 14f-(23) 14e-(20) 14g-(23)14h-(24) 14j-(22) 14g-(20) 14g-(22) 14i-(21)14i-(23) 14i-(22) 14i-(21)14j-(20)Ampicillin (50 µg) 23 22 21 19 --Chloramphenicol(50 µg) 22 23 21 20 --Norfloxacin (50 µg) 24 21 23 22 --Greseofulvin (50 µg) -- -- -- -- 23215

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PublicationsLIST OF PAPER PUBLISED.1. Synthesis and antimicrobial activity of 1-(aroyl/arylsulpho/arylaminomethyl)-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.(M. D. Savaliya, J. G. Dobaria, V. N. Patolia, A. U. Patel, D. M. Purohit*)Organic Chemistry, An Indian journal; Vol. 5(1), 2009 [100-103].LIST OF PAPER SUBMITTED FOR PUBLICATION:1. Synthesis and antimicrobial activity of 1-N-(aroylamino/arylsulphonamido/arylaminomethylamino)-4-[(4',4"-difluorodiphenyl)-methyl]-piperazines.(M. D. Savaliya, J. G. Dobaria, V. N. Patolia and D. M. Purohit*)( ARKIVOC)2. Synthesis and antimicrobial activity of 1-N-(arylidineamino/1-Narylmethylamino-4-[(4’,4”-difluorodiphenyl)-methyl]-piperazines.(M. D. Savaliya, J. G. Dobaria, V. N. Patolia, D. M. Purohit*)(Indian Journal of Heterocyclic Chemistry)3. Synthesis and biological screening of 1-N-{4'-[(4",4"'-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-arylidene-2-phenyl-5-oxo-imidazolines.(M. D. Savaliya, J. G. Dobaria, V. V. Bhuva, V. N. Patolia, D. M. Purohit*)(Organic Chemistry, An Indian journal)4. Synthesis and biological screening of 1-N-{4'-[(4",4"'-difluorodiphenyl)-methyl]-piperazine-1'-yl}-4-arylidene-2-(4""-methoxyphenyl)-5-oxo-imidazolines.(M. D. Savaliya, J. G. Dobaria, V. V. Bhuva, V. N. Patolia, D. M. Purohit*)(Organic Chemistry, An Indian journal)247