Studies on quinolone antibacterials. V. Synthesis and antibacterial activity of chiral 5-amino-7-(4-substituted-3-amino-1-pyrrolidinyl)-6- fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acids and derivatives.
We previously demonstrated that 5-amino-7-(3-amino-1-pyrrolidinyl) -1-cyclopropyl-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (7) has strong in vitro antibacterial activity even against quinolone-resistant bacteria. We examined optimization of the 3-aminopyrrolidine moiety of 7 by introduction of C-alkyl (Me, Et, Pr, di-Me, cyclopropyl) and N-alkyl groups (Me, di-Me). C-Alkylation at the 4-position of the 3-aminopyrrolidine moiety enhanced in vitro and in vivo antibacterial activity. (S)-5-Amino-7-(7-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-pyr rolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (15b) showed strong antibacterial activity (in vitro antibacterial activity including quinolone-resistant bacteria is 4 times more potent than that of ciprofloxacin (CPFX) (1); in vivo antibacterial activity is 1.5 to 20 times more potent than that of CPFX (1)) and reduced quinolone toxicity (free from both phototoxicity at a dosage of 30 mg/kg in guinea pigs (i.v.) and convulsion when coadministered with 4-biphenylacetic acid at a dosage of 20 micrograms in rats (i.c.v.)). Their selectivity between DNA topoisomerase II (derived from eukaryotic cells) and DNA gyrase (derived from bacterial cells) was about 3000-fold.
Yoshida
T
T
Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
Yamamoto
Y
Y
Orita
H
H
Kakiuchi
M
M
Takahashi
Y
Y
Itakura
M
M
Kado
N
N
Yasuda
S
S
Kato
H
H
Itoh
Y
Y
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004926:Escherichia coli / Q000187:drug effects; D024841:Fluoroquinolones; D006168:Guinea Pigs; D007711:Klebsiella pneumoniae / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D018079:Receptors, GABA; D059005:Topoisomerase II Inhibitors