NOVEL FLUOROQUINOLONE ANTIBACTERIAL AGENTS CONTAINING OXIME-SUBSTITUTED (AMINOMETHYL)PYRROLIDINES - SYNTHESIS AND ANTIBACTERIAL ACTIVITY OFO-4-OXO-1,4-DIHYDRO[1,8]NAPHTHYRIDINE-3-CARBOXYLIC ACID (LB20304)

New pyrrolidine derivatives, which bear an alkyloxime substituent in t he 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quino linecarboxylic acids to produce a series of new fluoroquinolone antiba cterials. These fluoroquinolones were found to possess potent antimicr obial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variati ons at the C-8 position of the quinolone nucleus included fluorine, ch lorine, nitrogen, methoxy, and hydrogen atom substitution. The activit y imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C-5-NH2) > F (C-5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strai ns, activity was in the order F (C-5-NH2) > naphthyridine = F (C-5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly imp roved the pharmacokinetic parameters of the novel quinolones. Among th ese compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical prope rties. The MICs (mu g/mL) of LB20304, compound 30, and ciprofloxacin a gainst several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128) , Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, a nd 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobact er cloacae P99 (0.008, 0.031, and 0.008), Acinobacter calcoaceticus 15 473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.