MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety.
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
Nakayama
Kiyoshi
K
Daiichi Pharmaceutical Co., Ltd, 1-16-13, Kitakasai, Edogawa, Tokyo 134-8630, Japan. nakaygoi@daiichipharm.co.jp
Kuru
Noriko
N
Ohtsuka
Masami
M
Yokomizo
Yoshihiro
Y
Sakamoto
Atsunobu
A
Kawato
Haruko
H
Yoshida
Ken-ichi
K
Ohta
Toshiharu
T
Hoshino
Kazuki
K
Akimoto
Katsuya
K
Itoh
Junko
J
Ishida
Hiroko
H
Cho
Aesop
A
Palme
Monica H
MH
Zhang
Jason Z
JZ
Lee
Ving J
VJ
Watkins
William J
WJ
D000179:Acrylates / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004355:Drug Stability; D007536:Isomerism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D010777:Photochemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000179:Acrylates; D001425:Bacterial Outer Membrane Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; D011743:Pyrimidines; C036658:acrylic acid