title: Synthesis and structure-activity relationships of 5-substituted 6,8-difluoroquinolones, including sparfloxacin, a new quinolone antibacterial agent with improved potency.
abstract: A series of 5,7-disubstituted 1-cyclopropyl-6,8-difluoro-4(1H)-oxoquinoline-3-carboxylic acids (10-36) were prepared; the C-5 substituent in these compounds comprised halo, hydroxy, mercapto, and amino groups and the C-7 functional group included variously substituted piperazines. In vitro antibacterial screening results indicated that the amino group was optimal among the C-5 substituents. A combination of the C-5 amino group and the C-7 3,5-dimethylpiperazinyl appendage in this series conferred the best overall antibacterial property with lack of adverse drug interactions. Compound 36k [named sparfloxacin, originally AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)- 4(1H)-oxoquinoline-3-carboxylic acid] was superior to ciprofloxacin in both in vitro and in vivo potency and hence was selected as a promising candidate for an improved therapeutic agent.
authors.affiliation: Research Laboratories, Dainippon Pharmaceutical Company, Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyamoto
authors.forename: J
authors.initials: J
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Chiba
authors.forename: H
authors.initials: H
authors.lastname: Egawa
authors.forename: K
authors.initials: K
authors.lastname: Shibamori
authors.forename: A
authors.initials: A
authors.lastname: Minamida
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimura
authors.forename: H
authors.initials: H
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Kataoka
authors.forename: M
authors.initials: M
authors.lastname: Fujita
mesh_terms: D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004347:Drug Interactions; D024841:Fluoroquinolones; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010654:Phenylbutyrates / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000188:drug therapy; D051381:Rats; D013290:Streptococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D042462:4-Quinolones; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D010654:Phenylbutyrates; C010725:fenbufen; D013806:Theophylline; C061363:sparfloxacin