STUDIES ON QUINOLONE ANTIBACTERIALS .4. STRUCTURE-ACTIVITY-RELATIONSHIPS OF ANTIBACTERIAL ACTIVITY AND SIDE-EFFECTS FOR 5-SUBSTITUTED OR 8-SUBSTITUTED AND YCLOPROPYL-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXYLIC ACIDS

A series of yclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids b earing various substituents (H, F, Cl, Me, OH, OMe, OEt, OCH2F, OCHF2, OCF3, SMe) at the C-8 position was prepared and evaluated for in vitr o antibacterial activity against both standard laboratory strains and bacteria resistant to quinolones such as ciprofloxacin (CPFX, 1) and o floxacin (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 bact eria. But these four compounds caused injury to the chromosomes of mam malian cells at a concentration of 100 mu g/ml. Next, a series of quin olones having various substituents (H, Cl, Me, NH2, NHMe, NMe(2)) at t he C-5 position was prepared and evaluated for antibacterial activity and injurious effect on the chromosome. We found that the 5-amino-8-me thyl compound (8d) showed strong antibacterial activity (in vitro anti bacterial 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 quinolone-type toxicity (free from bot h phototoxicity at a dosage of 30 mg/kg in guinea pigs (i.v.) and conv ulsion-inducing activity when coadministered with fenbufen at a dosage of 100 mg/kg in mice (i.p.)).