title: 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.
abstract: 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.
authors.affiliation: Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Orita
authors.forename: M
authors.initials: M
authors.lastname: Kakiuchi
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Itakura
authors.forename: N
authors.initials: N
authors.lastname: Kado
authors.forename: S
authors.initials: S
authors.lastname: Yasuda
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
mesh_terms: 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
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D018079:Receptors, GABA; D059005:Topoisomerase II Inhibitors