Studies on 8-methoxyquinolones: Synthesis and antibacterial activity of 7-(3-amino-4-substituted)pyrrolidinyl derivatives

A series of 8-methoxyquinolones bearing 3-amino-4-methylpyrrolidines or 3-a mino-4-fluoromethylpyrrolidines at the C-7 position was synthesized and the ir physicochemical and biological properties were evaluated. All of the com pounds synthesized showed more potent activity than LVFX (3) against both g ram-positive and negative bacteria. Increases In lipophilicity of these com pounds had desirable effects on their potency of single intravenous toxicit y and pharmacokinetic profiles in animals. Among the compounds synthesized, 1-fluorocyclopropyl derivatives 17 and 20, and 7-(cis-3-amino-4-fluorometh ylpyrrolidinyl) derivative 19 (DC-756h) showed negative responses in the mi cronucleus test in mice while 1-cyclopropyl-7-(3-aminopyrrolidinyl) derivat ive 16 showed a positive response. These results suggested that the introdu ction of a fluorine atom into the 3-aminopyrrolidinyl substituent resulted in favorable influence on genetic toxicity as well as into the N-1 cyclopro pyl substituent.