Title of article :
MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: Highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate Original Research Article
Author/Authors :
Ken-ichi Yoshida، نويسنده , , Kiyoshi Nakayama، نويسنده , , Masami Ohtsuka، نويسنده , , Noriko Kuru، نويسنده , , Yoshihiro Yokomizo، نويسنده , , Atsunobu Sakamoto، نويسنده , , Makoto Takemura، نويسنده , , Kazuki Hoshino، نويسنده , , Hiroko Kanda، نويسنده , , Hironobu Nitanai، نويسنده , , Kenji Namba * ، نويسنده , , Kumi Yoshida، نويسنده , , Yuichiro Imamura، نويسنده , , Jason Z. Zhang، نويسنده , , Ving J. Lee، نويسنده , , William J. Watkins، نويسنده ,
Abstract :
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the β-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.
Keywords :
Efflux pump inhibitor , Drug resistance , MexAB-OprM efflux pump , Pseudomonas aeruginosa
