Effects of skeletal modifications of ciprofloxacin on ... - ResearchGate

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JOURNAL <strong>of</strong> CHINESE CLINICAL MEDICINE VOLUME 2|NUMBER 4|April 2007 (61),56 (100). 1 唱Cyclopropyl唱6 唱fluoro唱7 唱[ 4唱( 4唱methoxybenzoyl )唱 1 唱piperazinyl]唱4唱oxo唱1, 4唱dihydro唱3唱quinoline car唱 boxylic acid (11) Yield:0畅79 g (79%);M.P.=170℃ ~172℃;IR nmax cm -1 : 3412 , 3016, 2930, 1719, 1602, 1467, 1433, 1255,1167; 1 H -NMR ( 300 MHz -DMSO -d6):d 8畅6 (s,H,H -2 ) , 7畅9(d,1 H, J =6畅6 Hz,H -5), 7畅6 (d,1H,J =5畅0 Hz.1,H -8 ) , 7畅4 (d,2H, J = 6畅3 Hz,H -3 ′,7′),7畅1(d,2 H,J =6 畅5 Hz, H -4 ′, 6′),3畅8(s,2H, H -11),3畅7 (s,3H, H -8 ′),3畅3 ( s,4H, H -16,20),2畅4 (s,4H, H -17,19),1畅3 ( d,2H,J =4畅9 Hz, H -13),0畅8(s,2H, H -12); EIMS m /z (% rel.abund.):465 (M + ,2畅6),420 (4),289 (3),271 (2),230 (3畅6),201 (2),151 (33),135 (74),92 (33),77 (47),56 (50). 1 唱Cyclopropyl唱6 唱fluoro唱4 唱oxo唱7 唱[ 4 唱( 3, 4, 5唱trime唱 thoxybenzoyl )唱1唱piperazinyl ]唱1, 4唱dihydro唱3唱quin唱 oline carboxylic acid (12) Yield:0畅43 g (43%);M.P.= 280℃ ~282 ℃;IR nmax cm -1 : 3048 , 3056, 2919, 2855, 1720, 1298, 1622, 1486,1251, 1210; 1 H -NMR (300 MHz -DMSO - d 6 ):d 15畅1 (s,1H,H -14) ,8畅6 (s,1H,H -2),7畅8 ( d,1H,J =4畅7 Hz,H -5),7畅5 (d,1H,J =4畅7 Hz,H -7),7畅6(d,2H, J =2 畅2 Hz H -3 ′,7′),4畅1(s, 1 H,H -11),3畅7 (s,9H, H -8 ′,9′,10′),3畅6 (s, 4 H,H -16,20),2畅3 (s,4H, H -17,19),1畅9 (s, 2 H,H -13),1畅2 (s,4H, H -12);EIMS m /z (% rel.abund.):391 (M + ,6),279 (27),197 (2畅5), 167 (53) ,149 ( 100) . 1 -Cyclopropyl -6唱fluoro唱7唱[ 4唱( 1唱naphthoyl )唱1唱 piperazinyl ]唱4唱oxo唱1, 4 唱dihydro唱3唱quinoline car唱 boxylic acid Yield:0畅70 g (70%);M.P.= 283℃ ~285 ℃;IR nmax cm -1 : 3480 , 3055, 2931, 1725, 1625, 1478, 1435, 1386,1249, 1204; 1 H -NMR (300 MHz -DMSO - d 6 ):d 15畅2 (s,1H,H -14) ,8畅6 (s,1H,H -2),8畅0 ( d,1H,J =6畅3 Hz,H -5 ) , 7畅5(d,1H,J =5畅0 Hz, H -8),7畅8(t,1H,J =8畅4 Hz,H -8 ′) ,7畅7 (d,1H, J =8畅4 Hz,H -6 ′),7畅66 ( d,1H, J =8畅4 Hz, H - 9′),7畅61 (d,1H,J =8畅3 Hz,H -5 ′),7畅5(d,1H,J =8畅3 Hz, H -3 ′),7畅4(t,1H, J =8 畅4 Hz, H -7 ′) 7畅1 (t,1H, J =8畅3 Hz, H -3′),3畅8 (s,1H, H - 11) ,3畅5 (s,4H, H -16,20),2畅4 (s,4H, H -1 7 , 19),1畅2 (s,2H,H -13) ,0畅9 (s,2 H,H -12 ) ; EIMS m /z (% rel.abund.):485 (M + ,0畅39),441 (19), 286 ( 13 ) , 257 ( 36 ) , 245 ( 2畅8),55 (56),127 (61),101 (3),56 (100). Antibacterial Studies ( In vitro) 191 The synthesized compounds were screened for antibac唱 terial activity against the number <strong>of</strong> Gram -negative organisms including Klebsiella pneumoniae,Escherichi唱 a coli, Proteus mirabilis, Shigella dysenteriae, Pseudo唱 monas aeruginosa, Salmonella typhi, Salmonella typhi para,A Salmonella typhi para B and Gram -positive organisms like Staphylococcus aureus and Bacillus sub唱 tilis by using literature protocol [18] .In the agar well dif唱 fusion method,wells were duged in the media with the help <strong>of</strong> a sterile metallic borer with contres at least 24 mm part.Two to eight hours old bacterial inoculums containing approximately 104 ~106 colony forming units ( CFU) /ml were spread on the surface <strong>of</strong> nutrient agar with the help <strong>of</strong> a sterile cotton swab.Cotton swab was rotated firmly against the upper inside well <strong>of</strong> the tube to express excess fluid.Entire agar surface <strong>of</strong> the plate was streaked with the swab three times turning the plate 60°between each streaking.Recommended concentration <strong>of</strong> the test sample (2 mg /ml <strong>of</strong> DMSO) was then added in their respective wells.Other wells supplemented with DMSO and reference antibacterial drugs serving as negative and positive controls,respec唱 tively.The plates were incubated immediately at 37 ℃ for 14 ~19 horlater,if necessary.Antibacterial activity was determined by measuring the diameter <strong>of</strong> zones showing complete inhibition ( mm).Growth inhibition was calculated with reference to positive control. Fungicidal Bioassay ( In vitro) The synthesized compounds were tested for antifungal activity against the fungi including Aspergillus flavus, Trichophyton longifusis,Candida albicans,Microsporum canis,Fusraium solani and Candida glaberata.Ampho唱 tericin B and miconazol were used as standard drugs. For tube diffusion test 12 mg <strong>of</strong> sample was dissolved in 1 ml <strong>of</strong> DMSO serving as stock solution.Sabouraud dextrose agar ( Oxoid, Hampshire, England ) was seeded with 105 CFU /ml fungal spore suspensions and
192 JOURNAL <strong>of</strong> CHINESE CLINICAL MEDICINE VOLUME 2|NUMBER 4|April 2007 transferred to Petri plates.Discs soaked in 20 ml (10 mg /ml in DMSO) <strong>of</strong> all compounds were placed at different positions on the agar surface.The plates were incubated at 32 ℃ for seven days.The results were recorded as zones <strong>of</strong> inhibition in mm [19] . Cytotoxicity Bioassay ( In vitro) Twenty mg <strong>of</strong> the test sample was dissolved in the re唱 spective organic solvent.From this stock solution 5,50, 500 μl were transferred to vials (3 vials /concentra唱 tion).The final concentration was 10,100,1000 μg / ml respectively, and the solvent was evaporated over night. Brine shrimp ( Artemia salina leach ) eggs were hatched and after two days, when shrimp larvae were ready,1 ml <strong>of</strong> seawater and 10 shrimps were added to each vial (30 shrimps /dilution) and the volume was adjusted with seawater to 5 ml per vial.After 24 hthe [ 20] number <strong>of</strong> survivors was counted and data were ana唱 lyzed by Finney computer program to determine the [21 ] LD50 . RESULTS AND DISCUSSION Our synthetic pathway was based on the preparation <strong>of</strong> different derivatives <strong>of</strong> cipr<strong>of</strong>loxacin [1] by treating it with respective acid chloride in tetrahydr<strong>of</strong>uran ( THF) in the presence <strong>of</strong> triethylamine ( TEA) as a base.The resultant mixture was refluxed and the completion <strong>of</strong> the reaction was monitored by TLC analysis.The struc唱 [2 ~13] tures <strong>of</strong> all the synthesized derivatives were con唱 firmed by using the sophisticated spectroscopic tech唱 niques like 1H唱NMR, IR and EI mass spectrometry ( Scheme 1,Table 1). Antimicrobial Activity <strong>of</strong> Cipr<strong>of</strong>loxacin Derivatives [ 2 ~13] All the synthesized compounds were screened for their antimicrobial affects against 8 Gram唱negative in唱 cluding Klebsiella pneumoniae, Escherichia coli, Pro唱 teus mirabilis, Shigella dysenteriae, Pseudomonas aeruginosa,Salmonella typhi, Salmonella typhi para A and Salmonella typhi para B as well as two Gram唱posi唱 tive organisms namely Staphylococcus aureus and Ba唱 cillus subtilis.The results <strong>of</strong> in vitro antibacterial activi唱 ty are collected in Table 2. Table 1 The Structures <strong>of</strong> All the Synthesized Dervatives S.No. R Yield (%) 2 -CH 3 75 3 -OC 2 H 5 87 4 -CHCl 2 51 5 -C( CH 3 ) 3 80 6 -C 7 H 15 44 7 -C 8 H 17 73 8 -C 9 H 19 68 9 53 10 Cl 11 OMe 79 12 OM e OM e OMe 13 70 80 24
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