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KMID : 0370019950090000035
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Chung-Ang Journal of Pharmacal Sciences
1995 Volume.9 No. 0 p.35 ~ p.66
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Syntheses and Antimicrobial Activities of Hybrid Bivalent Ligand Quinolones with β-Lactam Antibiotics
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Abstract
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Eight new hybrid bivalent ligands of β-lactam-fluoroquionolone tht contain two different types of pharmacophore in a single molecule wrer synthesized. One of the pharmacophores is a series of β-lactams(ampicillin, amoxicillin, cephalexin, cefadroxil), and the other is a morfloxacin or a enoxacin.
This class of compounds exhibited a broad antivacterial spectrum derived from both β-lactam-like and fluoroquinloone-like acivities, suggesting a dual mode of action.
1-Ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(4-t-butoxycarbonyl-1-piperazinyl)-3-quinoline(or naphthyridine) carboxylic acids([1], [2]) were prepared by the reaction of 7-(1-piperazinyl)-fluoroquinolones with di-tbutydicarbonate.
Treatment of compound [1], [2] with p-nitrobenzyl bromide afforded 7-(4-BOC-1-piperazinyl)-fluoroqu-inolones PNB esters([3], [4]). 7-(1-Piperazinyl)-flrouoquinlone PNB ester TFA salts([5], [6]) were prepared by the reaction of compound [3], [4] with trifluoroacetic acid.
Two 7-(4-succinyl-1-piperazinyl)-fluoroquinolone PNB esters ([7], [8]) were obtained by the reaction of compound [5], [6] with succinic anhydride.
Two active esters of 7-(4-succinyl-1-piperazinyl)-flroroquinolone PNB ester ([9], [10]) were synthesized by the reaction of compound [7], [8] with hydroxy succinimide in the presenc of dicyclohexylcarbodiimide.
Eight hybrid bivalent ligands of β-lactam-fluoroquinolone PNB esters ([11], [18]) were prepared by the reaction of the aqueous salts of ampicillin, amoxicillin, cephalexin, cefadroxil.
Eight hydrid bivalent ligands of β-lactam-fluoroquilolone )[19], [26]) were obtained by the reduction of compound [11]-[19] with hydrogen in the presence of 10% Pd/C
The synthesized compounds were evaluated for their antimicrobial activities in vitro against staphylococcus aureus, Streptococcus pyogenes, Strepococcus faecium, Esherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, Klebsiella oxytoca, Enterobacter cloaoae. The results obtained were as follows ;
1. The most active compound [20], [1-(p-hydroxyphenyl)-1-(1-ethyl-e-carboxy-6-fluoro-1, 4-dihydro-4-oxo-7-quinolinyl)-4-piperazinyl)-4-succinylamido] acetamido penicillanic acid, exhibited the growth inhibitory activity at concentration of 1.563㎍/㎖ against S. pyogenes 308A, 0781㎍/㎖ against S. aureus, 0.195㎍/㎖ against K. oxytoca 1082E, 0.049㎍/㎖ against E. cloacae 1321E.
2. Most of norfloxacin analogues showed more potent antimicrobial activities in vitro than those of enoxacin analogues.
3. Compounds that contain penicillin(ampicillin or amoxicillin) showed more petent antivicrobial activities in vitro than those that contain cephalosporin(cephalixin or cefadroxil).
4. Compared to β-lactam antibiotics, the synthesized compounds were more active in vitro against Gram- negative organisms and against Pseudomonas.
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KEYWORD
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