Studies on Quinolone Antibacterials. IV. Structure-Activity Relationships of Antibacterial Activity and Side Effects for 5- or 8-Substituted and 5,8-Disubstituted-7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-l,4-dihydro-4-oxoquinoline-3-carboxylic Acids

摘要

A series of 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyI-l,4-dihydro-4-oxoquinoline-3-carboxylic acids bearing various substituents (H, F, Cl, Me, OH, OMe, OEt, OCH2F, OCHF2, OCF3, SMe) at the C-8 position was prepared and evaluated for in vitro antibacterial activity against both standard laboratory strains and bacteria resistant to quinolones such as ciprofloxacin (CPFX, 1) and ofloxacin (OFLX, 2) from clinical isolates. The 8-methyl (8a), 8-fluoro (9a), 8-chloro (10a) and 8-methoxy (12a) compounds were 4 times more potent than CPFX (1) against both gram-positive and gram-negative bacteria. But these four compounds caused injury to the chromosomes of mammalian cells at a concentration of 100/ig/ml. Next, a series of quinolones having various substituents (H, Cl, Me, NH2, NHMe, NMe2) at the C-5 position was prepared and evaluated for antibacterial activity and injurious eifect on the chromosome. We found that the 5-amino-8-methyl compound (8d) showed strong antibacterial activity (in vitro antibacterial activity of 8d is 4 times more potent than that of CPFX (1) against both gram-positive and gram-negative bacteria), reduced injury to the chromosome, and reduced quinolonc-typc toxicity (free from both phototoxicity at a dosage of 30mg/kg in guinea pigs (i.v.) and convulsion-inducing activity when coadministercd with fenbufen at a dosage of 100 mg/kg in mice (i.p.)).