10.1021/jm970202e.s001 Chang Yong Hong Chang Yong Hong Young Kwan Kim Young Kwan Kim Jay Hyok Chang Jay Hyok Chang Se Ho Kim Se Ho Kim Hoon Choi Hoon Choi Do Hyun Nam Do Hyun Nam Yong Zu Kim Yong Zu Kim Jin Hwan Kwak Jin Hwan Kwak 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)<sup>†</sup><sup>,1</sup> American Chemical Society 1997 MIC quinolone nucleus Antibacterial hydrogen atom substitution substituent fluoroquinolone pyrrolidine epidermidi NH 2 oxime order F desoximino compound 30 OMe naphthyridine Cl pharmacokinetic C 5 methicillin MRSA LB aureus Aminomethyl organism 1997-10-24 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/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-carb/3682902 New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant <i>Staphylococcus aureus </i>(MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C<sub>5</sub>-NH<sub>2</sub>) > F (C<sub>5</sub>-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C<sub>5</sub>-NH<sub>2</sub>) > naphthyridine = F (C<sub>5</sub>-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 <b>30</b>. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound <b>20</b> (LB20304) showed the best <i>in vivo</i> efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (μg/mL) of LB20304, compound <b>30</b>, and ciprofloxacin against several test organisms are as follows:  <i>S. aureus</i> 6538p (0.008, 0.031, and 0.13), methicillin resistant <i>S. aureus</i> 241 (4, 16, and 128), <i>Streptococcus epidermidis</i> 887E (0.008, 0.016, and 0.13), methicillin resistant <i>S. </i><i>epidermidis </i>178 (4, 32, and 128), <i>Enterococcus faecalis</i> 29212 (0.063, 0.13, and 1), <i>Pseudomonas aeruginosa </i>1912E (0.25, 0.5, and 0.13), <i>Escherichia coli </i>3190Y (0.008, 0.016, and 0.008), <i>Enterobacter cloacae </i>P99 (0.008, 0.031, and 0.008), <i>Actinobacter calcoaceticus</i> 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.