K. Araki et al., QUINOLONE ANTIMICROBIAL AGENTS SUBSTITUTED WITH MORPHOLINES AT THE 7-POSITION - SYNTHESES AND STRUCTURE - ACTIVITY RELATIONSHIPS, Journal of medicinal chemistry, 36(10), 1993, pp. 1356-1363
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.