jm970202e_si_001.pdf (423.48 kB)
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)†,1
journal contribution
posted on 1997-10-24, 00:00 authored by Chang Yong Hong, Young Kwan Kim, Jay Hyok Chang, Se Ho Kim, Hoon Choi, Do Hyun Nam, Yong Zu Kim, Jin Hwan KwakNew 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
Staphylococcus aureus (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 (C5-NH2) > F
(C5-H) > naphthyridine > Cl = OMe = H against
Gram-positive organisms. In the case of
Gram-negative strains, activity was in the order F
(C5-NH2) > naphthyridine = F
(C5-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 improved the pharmacokinetic parameters of the
novel quinolones.
Among these compounds, compound 20 (LB20304) showed the
best in vivo efficacy and
pharmacokinetic profile in animals, as well as good physical
properties. The MICs (μg/mL) of
LB20304, compound 30, and ciprofloxacin against 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, and 0.13), Escherichia coli 3190Y
(0.008, 0.016, and 0.008), Enterobacter cloacae
P99 (0.008, 0.031, and 0.008), Actinobacter
calcoaceticus 15473 (0.063, 0.13, and 0.25). On
the
basis of these promising results, LB20304 was selected as a candidate
for further evaluation.