Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines: synthesis and antibacterial activity of 7-(4-(aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (LB20304)

摘要: New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and aminomethyl 3-position of ring, have been synthesized coupled with various quinolinecarboxylic acids to produce a series new fluoroquinolone antibacterials. These fluoroquinolones were found possess potent antimicrobial activity against both Gram-negative Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at C-8 position quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, hydrogen atom substitution. The imparted substituted by was order F (C5-NH2) > (C5-H) naphthyridine Cl = OMe H organisms. In case strains, OMe. advantages provided newly introduced oxime group quinolones clearly demonstrated their comparison desoximino compound 30. addition, moiety greatly improved pharmacokinetic parameters novel quinolones. Among these compounds, 20 (LB20304) showed best vivo efficacy profile animals, as well good physical properties. MICs (microgram/mL) LB20304, 30, ciprofloxacin several test organisms are follows: S. 6538p (0.008, 0.031, 0.13), 241 (4, 16, 128), Streptococcus epidermidis 887E 0.016, 178 32, Enterococcus faecalis 29212 (0.063, 0.13, 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, Escherichia coli 3190Y 0.008), Enterobacter cloacae P99 Actinobacter calcoaceticus 15473 0.25). On basis promising results, LB20304 selected candidate for further evaluation.