Abstract
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.
Keywords
ChemistryAntibacterial activityCarboxylic acidStereochemistryAntibacterial agentCombinatorial chemistryOrganic chemistryAntibioticsBacteriaBiochemistry
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Publication Info
- Year
- 1984
- Type
- article
- Volume
- 27
- Issue
- 3
- Pages
- 292-301
- Citations
- 90
- Access
- Closed
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Cite This
Junichi Matsumoto,
T. MIYAMOTO,
Akira Minamida
et al.
(1984).
1,4-Dihydro-4-oxopyridinecarboxylic 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.
Journal of Medicinal Chemistry
, 27
(3)
, 292-301.
https://doi.org/10.1021/jm00369a011
Identifiers
- DOI
- 10.1021/jm00369a011