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JOURNAL <strong>of</strong> CHINESE CLINICAL MEDICINE VOLUME 2|NUMBER 4|April 2007 HClHN F N O N THF,TEA,RCOX 70 ℃ X =Cl COOH R 5%aq.NaHCO 3 room temp erature. O N F N Scheme 1 Table 2 In vitro Antimicrobial Activity Results <strong>of</strong> Cipr<strong>of</strong>loxacin (1) and Its Derivatives (2 -13) against Gram唱negative and Gram唱positive Bacteria ( zone <strong>of</strong> inhibition in mm) Gram唱negative HN 2-13 O N F N 1 COOH O N COOH Compound No. 1 2 3 4 5 6 7 8 9 10 11 12 13 Escherichia coli 28 19 6 10 6 6 13 16 26 8 7 20 9 Pseudomonas aeruginosa 23 17 13 10 17 8 9 8 11 8 8 16 8 Salmonella typhi 28 19 7 18 13 12 18 12 22 6 7 18 6 Salmonella typhi para A 30 22 11 24 15 13 15 13 20 7 8 20 7 Salmonella typhi para B 32 16 12 18 13 10 10 8 18 8 6 17 11 Proteus mirabilis 20 11 8 10 5 11 11 9 14 8 8 13 9 Klebsiella pneumoniae 25 22 10 20 12 9 12 8 24 6 7 15 8 Shigella dysenteriae 26 13 13 19 13 8 8 10 10 9 10 9 10 Gram唱positive Bacillus subtilis 27 25 10 16 8 7 14 10 17 10 9 14 10 Staphylococcus aureus 30 20 6 8 9 14 12 11 23 7 7 22 6 It was found that the structural analogues <strong>of</strong> cipro唱 floxacin (1) showed varying degree <strong>of</strong> antimicrobial activity against all the tested bacterial strains.Com唱 pounds 9 and 2 showed good activities against Esche唱 richia coli,however,compound 2 exhibited comparable activity against Bacillus subtilis.Good activities <strong>of</strong> com唱 pounds 2,9,and 12 were observed against Staphylococ唱 cus aureus,while compound 9 showed good activity a唱 gainst Salmonella typhi.Four derivatives 2,4,9,and 12 exhibited good activities against Salmonella typhi para A,where compound 2,4,and 9 were found to be active against Klebsiella pneumoniae.Compound 9 in the case 193 <strong>of</strong> Klebsiella pneumoniae showed almost equivalent de唱 gree <strong>of</strong> activity compared to the cipr<strong>of</strong>loxacin [1] . In general,the compound 2,4,9,and 12 showed good activities against Escherichia coli, Bacillus subti唱 lis, Staphylococcus aureus,Salmonella typhi,Salmonel唱 la typhi para A and Klebsiella pneumoniae.Comparison <strong>of</strong> the activities <strong>of</strong> different analogues <strong>of</strong> cipr<strong>of</strong>loxacin (1) indicates that the amidic linkage at piperazine moiety may be responsible for the changes in the anti唱 microbial properties <strong>of</strong> the parent molecule.A careful selection <strong>of</strong> the substituent at the nitrogen <strong>of</strong> piperazine nucleus may result into a more active antibiotic based
194 JOURNAL <strong>of</strong> CHINESE CLINICAL MEDICINE VOLUME 2|NUMBER 4|April 2007 Table 3 Results <strong>of</strong> Screening Cipr<strong>of</strong>loxacin (1) and its Derivatives (2 -13) for their Antifungal Activity in vitro ( zone <strong>of</strong> in唱 hibition in mm) Test fungi Compound No. A B 1 2 3 4 5 6 7 8 9 10 11 12 13 Trichophytonlongifusus 100 0 0 0 0 0 0 0 60 60 0 25 0 0 0 Candida albicans 100 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Aspergillus flavus 0 100 0 0 0 0 0 0 60 0 0 45 0 0 0 Microsporum canis 100 0 0 0 0 0 0 0 55 55 0 50 0 50 0 Fusarium solani 100 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Candida glaberata 100 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Note:A =Miconazole;B =Amphotericine B on cipr<strong>of</strong>loxacin (1).These preliminary studies provide us lead compounds like 2,4,9,and 12 for further modi唱 fications at nitrogen <strong>of</strong> piperazine or other active posi唱 tions like carboxylic acid residue or the ketonic carbon唱 yl function.It may be envisioned that the <strong>modifications</strong> at nitrogen <strong>of</strong> piperazine residue and other two seem唱 ingly active positions may result into a better antibiotic with the minimization <strong>of</strong> its side effects. Antifungal Activity An interesting feature <strong>of</strong> the present study is that when all synthesized compounds (1 ~12) along with cipro唱 floxacin (1) were randomly screened for 6 fungal strains i.e.Trichophyton longifusus,Candida albicans, Aspergillus flavus,Microsporumcanis,Fusarium solani and Candida glaberata,it is revealed that cipr<strong>of</strong>loxacin (1 ) was inactive against any <strong>of</strong> the fungal strains used.Nevertheless,compound 7 showed good activities against Trichophyton longifusus,Aspergillus flavus and Microsporumcanis.Compound 8 was found to be active against Trichophyton longifusus and Microsporum canis strains.Compound 10 showed moderate activities a唱 gainst Aspergillus flavus and Microsporum canis,while compound 12 was found to be moderately active against Microsporumcanis. Antifungal activity in cipr<strong>of</strong>loxacin analogues may open new avenues for designing antifungal agents based on cipr<strong>of</strong>loxacin (1) skeleton.For enhancing the anti唱 fungal strength <strong>of</strong> the lead molecules 7,8,10,and 12, either modification in the alkyl side chain <strong>of</strong> compound 6 and 7 or by varying the substitution <strong>of</strong> phenyl ring in compound 10 and 12.In addition,the synthetic modifi唱 cations on carboxyl group or ketonic carbonyl function may enhance the antifungal activity. Cytotoxic Activity Bioactive compounds are <strong>of</strong>ten toxic to Artemia salina ( leach, brine shrimp ) larvae.The bioassay method adopted is rapid and inexpensive which has been devel唱 oped for screening and monitoring <strong>of</strong> physiologically active compound. During this experiment etoposide is used as stan唱 dared drug and LD50 is found to be 0畅178 μg /ml while it has been found that neither cipr<strong>of</strong>loxacin nor its de唱 rivatives is cytotoxic. CONCLUSION The <strong>skeletal</strong> <strong>modifications</strong> <strong>of</strong> cipr<strong>of</strong>loxacin (1) showed a varying degree <strong>of</strong> antimicrobial activities particularly compound 2,4,9,and 12 exhibited promising antimi唱 crobial activities devoid <strong>of</strong> any toxicity and may be used as lead compounds for further investigations.Ad唱 ditionally compound 7,8,10,and 12 exhibited encoura唱 ging antifungal activities and provided a base to explore the antifungal activities <strong>of</strong> cipr<strong>of</strong>loxacin (1) skeleton containing molecules.Further research based on over preliminary results may lead to a new class <strong>of</strong> com唱 pounds having antifungalproperties. REFERENCES 1.Crumplin GC,Smith JT.Nalidixic acid bacterial chromosome replica唱 tion.Nature,1976,260 :643 -645.
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