title: MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: exploration of aromatic substituents.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. yoshi11v@daiichipharm.co.jp
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yokomizo
authors.forename: Masami
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: Makoto
authors.initials: M
authors.lastname: Takemura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kanda
authors.forename: Kenji
authors.initials: K
authors.lastname: Namba
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nitanai
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Zhang
authors.forename: Ving J
authors.initials: VJ
authors.lastname: Lee
authors.forename: William J
authors.initials: WJ
authors.lastname: Watkins
mesh_terms: 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
chemical_list: 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