title: Pyridonecarboxylic acids as antibacterial agents. IX. Synthesis and structure-activity relationship of 3-substituted 10-(1-aminocyclopropyl)-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]- 1,4-benzoxazine-6-carboxylic acids and their 1-thio and 1-aza analogues.
abstract: A series of the title compounds listed in Chart 1 have been synthesized to study the effects of 3-alkyl substituents on the antibacterial potency and in vivo efficacy of 10-(1-aminocyclopropyl)-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3 -de]-1,4-benzoxazine-6-carboxylic acid and its 1-thio and 1-aza variants. Compound (S)-1, which proved most active in vitro against five representative gram-positive and gram-negative organisms, was assayed in vivo using Staphylococcus aureus and Pseudomonas aeruginosa mouse infection models. It exhibited an excellent in vivo efficacy, being superior to ofloxacin and ciprofloxacin, and was then assayed for convulsion-inducing activity, mammalian cell cytotoxicity, and topoisomerase II inhibition. The biological results showed that (S)-1 displayed antibacterial and toxicological advantages over ofloxacin and ciprofloxacin. Compound (S)-1 and its methanesulfonate showed high serum concentrations after oral and intravenous administrations to mice.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Todo
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: F
authors.initials: F
authors.lastname: Iino
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuoka
authors.forename: M
authors.initials: M
authors.lastname: Takahata
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.forename: I
authors.initials: I
authors.lastname: Saikawa
authors.forename: H
authors.initials: H
authors.lastname: Narita
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy; D012640:Seizures / Q000139:chemically induced; D013203:Staphylococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D006845:Hydrocarbons, Fluorinated