A series of 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acids bearing various substituents (H, F, C1, 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 micrograms/ml. Next, a series of quinolones having various substituents (H, C1, Me, NH2, NHMe, NMe2) at the C-5 position was prepared and evaluated for antibacterial activity and injurious effect 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 quinolone-type toxicity (free from both phototoxicity at a dosage of 30 mg/kg in guinea pigs (i.v.) and convulsion-inducing activity when coadministered with fenbufen at dosage of 100 mg/kg in mice (i.p.)).
Quinolone Antibacterials. Part 4. Structure-Activity Relationships of Antibacterial Activity and Side Effects for 5-or 8-Substituted and 5, 8-Disubstituted-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-1,4dihydro-4-oxoquinoline-3-carboxylic Acids.-With a view to obtaining compounds with antibacterial activity, quinoline derivatives such as (XI) and (XIV) are synthesized. The preparation of the starting material (XII) is also described. Compound (XI) is the most potent compound in this series with reduced side effects compared to ciprofloxacin. Biological data are given and structure-activity relationships are discussed. -(YOSHIDA, T.; YAMAMOTO, Y.; ORITA, H.; KAKIUCHI, M.; TAKAHASHI, Y.; ITAKURA, M.; KADO, N.; MITANI, K.; YASUDA, S.; KATO, H.; ITOH, Y.; Chem.
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A Large-Scale Preparation of (3S,4S)-3-(tert-Butoxycarbonyl)amino-4-methylpyrrolidine and Its Analogues from L-Aspartic Acid.-The title compound (X), which is an interesting synthon for the preparation of quinoline antibacterial agents, is synthesized by an efficient method which is applicable to large-scale preparation. It is noteworthy that in this approach no lead(II) nitrate for the synthesis of (III) is needed. The corresponding ethyland propyl-derivatives of (X) are obtained by identical approaches with 28% and 31% overall yield, respectively. -(YOSHIDA, T.; TAKESHITA, M.; ORITA, H.; KADO, N.; YASUDA, S.; KATO, H.; ITOH, Y.; Chem.
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