QUINOLONE ANTIMICROBIAL AGENTS SUBSTITUTED WITH MORPHOLINES AT THE 7-POSITION - SYNTHESES AND STRUCTURE - ACTIVITY RELATIONSHIPS

A series of novel 7-substituted 1-cyclopropyl-6,8-difluoro- 1,4-dihydr o-4-oxo-3-quinolinecarboxylic acids have been prepared and tested for antibacterial activities and for convulsive activities in combination with nonsteroidal antiinflammatory drug. Structure-activity relationsh ips revealed that 7-(2-(aminomethyl)morpholino) derivative 28 had a be tter Gram-positive activity than the reference quinolones, such as cip rofloxacin, norfloxacin, and ofloxacin. Its Gram-negative activity was equipotent with those of norfloxacin and ofloxacin but was inferior t o that of ciprofloxacin. In mouse systemic infection models, 28 showed an excellent therapeutic efficacy which might result from the potent antibacterial activity and suitable physicochemical properties. Convul sive activities of 7-morpholino derivatives in combination with nonste roidal antiinflammatory drug fenbufen or its metabolite biphenylacetic acid markedly diminished as compared to those of 7-piperazino derivat ives in the electrophysiological, biochemical, and behavioral experime nts. These results suggest that 28 (Y-26611) is a novel quinolone with reduced neurotoxic excitatory adverse reaction.