MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: exploration of aromatic substituents.
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with aromatic substituents, were synthesized by the Suzuki cross-coupling method and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. By incorporating hydrophilic substituents onto the aryl nucleus, we found a morpholine analogue that possessed improved solubility, retained activity in vitro, and displayed potentiation activity in vivo in a rat model of P. aeruginosa pneumonia.
Yoshida
Ken-ichi
K
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. yoshi11v@daiichipharm.co.jp
Nakayama
Kiyoshi
K
Yokomizo
Yoshihiro
Y
Ohtsuka
Masami
M
Takemura
Makoto
M
Hoshino
Kazuki
K
Kanda
Hiroko
H
Namba
Kenji
K
Nitanai
Hironobu
H
Zhang
Jason Z
JZ
Lee
Ving J
VJ
Watkins
William J
WJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001398:Aztreonam / Q000737:chemistry / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D064704:Levofloxacin; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D026901:Membrane Transport Proteins; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D011743:Pyrimidines; D064704:Levofloxacin; D015242:Ofloxacin; D001398:Aztreonam