Pyridonecarboxylic acids as antibacterial agents. 2. Synthesis and structure-activity relationships of 1,6,7-trisubstituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids, including enoxacin, a new antibacterial agent.
The title compounds having nitro, amino, cyano, chloro, or fluoro as the C-6 substituent were prepared. Introduction of the chloro and cyano groups at C-6 was accomplished by the Sandmeyer reaction of 6-amino-1,8-naphthyridine derivatives 9 via their 6-diazonium salts. The reaction was extended to the synthesis of the 6-fluoro analogues, involving the Balz-Schiemann reaction of the diazonium tetrafluoroborate. Furthermore, a series of the 1-ethyl, 1-vinyl, 1-(2-fluoroethyl), and 1-(difluoromethyl) analogues of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids was prepared. 1-Pyrrolidinyl and, particularly, N-substituted or unsubstituted 1-piperazinyl groups were introduced as the C-7 variants. As a result of this study, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid (named enoxacin, originally AT-2266) was found to show the most broad and potent in vitro antibacterial activity, an excellent in vivo efficacy on systemic infections, and a weak acute toxicity. Structure-activity relationships of compounds with variations of substituents at C-1, C-6, and C-7 are also discussed.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D001424:Bacterial Infections / Q000188:drug therapy; D015365:Enoxacin; D004926:Escherichia coli / Q000187:drug effects; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009287:Naphthyridines; D015365:Enoxacin