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.