Quinolone antibacterial agents. Synthesis and structure-activity relationships of 8-substituted quinoline-3-carboxylic acids and 1,8-naphthyridine-3-carboxylic acids

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Abstract
A series of 7,8-disubstituted 1-cyclopropyl-6-fluoroquinoline-3-carboxylic acids, 7-substituted 1-cyclopropyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids, and 10-substituted 9-fluoropyridobenzoxazine-6-carboxylic acids has been prepared and evaluated for antibacterial activity. The side chains examined at the 7-position (benzoxazine 10-position) included piperazinyl (g), 3-aminopyrrolidinyl (a), 3-(aminomethyl)pyrrolidinyl (b), and alkylated 3-(aminomethyl)pyrrolidinyl (c-f). Variations at C-8 of the quinolone ring system included hydrogen, nitro, amino, fluorine, and chlorine. The relative enhancement of in vitro activities by the side chains on the 8-hydrogen quinolone and 1,8-naphthyridine against Gram-negative organisms was a > b > g > c-f. The activity imparted to the substituted quinolone nucleus by the 8-substituent was in the order F > Cl > naphthyridine > H > benzoxazine > NH2 > NO2. These trends were retained in vivo.