SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF SOME NOVEL 1-SUBSTITUTED ,4-DIHYDRO-4-OXO-7-PYRIDINYL-3-QUINOLINECARBOXYLIC ACIDS - POTENT ANTISTAPHYLOCOCCAL AGENTS

The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridine s with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinaline carboxylate has provided access to the corresponding 1-substituted ,4- dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The antibacteri al activity of these derivatives was studied with the finding that the optimal 1- and 7-position substituents for Gram positive activity are cyclopropyl and 4-(2,6-dimethylpyridinyl), respectively. We find that for the fluorine-substituted derivatives studied, the position of the fluorine on the quinolone nucleus or the number of fluorine atoms doe s not seem to be important for good Gram positive activity. For 1-cycl opropyl 7-(2,6-dimethyl-4-pyridinyl) derivatives, the 6-fluoro 4a, 8-f luoro 10d, 6,8-difluoro 10b, and 5,6,8-trifluoro 8, all provided equal antibacterial activity activity against Staphylococcus aureus ATCC 29 213. There is also a correlation between the substitution on the 7-(4- pyridinyl) group and the Gram positive activity, particularly for S. a ureus, clearly indicating that the 2,6-dimethylpyridinyl group is opti mal. The MIC(50) value for the most potent agents in this study agains t S. aureus ATCC 29213 is 0.008 mu g/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 mu g/mL, respect ively, against this organism.