Pyridonecarboxylic acids as antibacterial agents. VII. Synthesis and structure-activity relationship of amino- and hydroxyl-substituted 7-cycloalkyl and 7-vinyl derivatives of 1-cyclopropyl-6-fluoro-4-quinolone-3- carboxylic acid.
Novel C(7)-derivatives of 1-cyclopropyl-6-fluoro-4-quinolone carboxylic acid (3a-o) have been synthesized and evaluated for in vitro antibacterial activity. Compounds 3e (3-aminocyclobutyl), 3g (1-aminocyclopropyl), 3m ((2-aminomethyl)vinyl), and 3o ((1-aminomethyl)vinyl) showed significant inhibitory activity, comparable to that of ciprofloxacin, against gram-negative bacteria including P. aeruginosa. A good pharmacokinetic profile (serum and brain concentrations and urinary recovery) was obtained for the two cyclic compounds (3e and 3g), but that of the vinylic compounds (3m and 3o) was less favorable. Compound 3g was less toxic than 3e, ciprofloxacin, or ofloxacin in terms of acute toxicity and convulsion-induction.
Todo
Y
Y
Research Laboratories, Toyama Chemical Co., Ltd., Japan.
Nitta
J
J
Miyajima
M
M
Fukuoka
Y
Y
Ikeda
Y
Y
Yamashiro
Y
Y
Saikawa
I
I
Narita
H
H
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D001812:Blood-Brain Barrier; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents