title: Studies on 8-methoxyquinolones: synthesis and antibacterial activity of 7-(3-amino-4-substituted)pyrrolidinyl derivatives.
abstract: A series of 8-methoxyquinolones bearing 3-amino-4-methylpyrrolidines or 3-amino-4-fluoromethylpyrrolidines at the C-7 position was synthesized and their physicochemical and biological properties were evaluated. All of the compounds synthesized showed more potent activity than LVFX (3) against both gram-positive and negative bacteria. Increases in lipophilicity of these compounds had desirable effects on their potency of single intravenous toxicity and pharmacokinetic profiles in animals. Among the compounds synthesized, 1-fluorocyclopropyl derivatives 17 and 20, and 7-(cis-3-amino-4-fluoromethylpyrrolidinyl) derivative 19 (DC-756h) showed negative responses in the micronucleus test in mice while 1-cyclopropyl-7-(3-aminopyrrolidinyl) derivative 16 showed a positive response. These results suggested that the introduction of a fluorine atom into the 3-aminopyrrolidinyl substituent resulted in favorable influence on genetic toxicity as well as into the N-1 cyclopropyl substituent.
authors.affiliation: New Product Research Laboratories I, Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan. kawakanl@daiichipharm.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Kawakami
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Ohki
authors.forename: K
authors.initials: K
authors.lastname: Kimura
authors.forename: S
authors.initials: S
authors.lastname: Miyauchi
authors.forename: R
authors.initials: R
authors.lastname: Miyauchi
authors.forename: M
authors.initials: M
authors.lastname: Takemura
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009152:Mutagenicity Tests; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D015363:Quinolones