Article

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: exploration of aromatic substituents.

Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.
Bioorganic & Medicinal Chemistry (Impact Factor: 2.9). 01/2007; 14(24):8506-18. DOI: 10.1016/j.bmc.2006.08.037
Source: PubMed

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.

0 Bookmarks
 · 
98 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Members of the RND family of efflux pumps, such as AcrAB-TolC of Escherichia coli, play major roles in multi-drug resistance (MDR) in Gram-negative bacteria. A strategy to combat MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the Enterobacteriacaea. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin vs. E. coli AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC deficient strains. MBX2319 (3.13 μM) in combination with 0.016 μg/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of E. coli AB1157 by 10,000 fold after 4 h exposure, as compared to 0.016 μg/ml CIP alone. In contrast, phenyl-arginine-β-naphthylamide (PAβN), a known EPI, did not increase the bactericidal activity of 0.016 μg/ml CIP at concentrations as high as 100 μM. MBX2319 increased intracellular accumulation of the fluorescent dye H33342 in WT, but not in AcrAB-TolC deficient strains, and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against species of the Enterobacteriacaea and Pseudomonas aeruginosa. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens.
    Antimicrobial Agents and Chemotherapy 11/2013; · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A general and efficient palladium-catalyzed direct C3 alkenylation of 4H-pyrido[1,2-a]pyrimidin-4-ones using AgOAc/O2 as the oxidant has been developed. A variety of 4H-pyrido[1,2-a]pyrimidin-4-ones were successfully coupled with acrylate esters, styrenes, methylvinylketone, and acrylamide in moderate to excellent yields. The reaction exhibited complete regio- and stereoselectivity. This transformation provides an attractive new approach to functionalize 4H-pyrido[1,2-a]pyrimidin-4-ones.
    Chemistry - An Asian Journal 07/2014; · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multidrug resistance (MDR) refers to the capability of bacterial pathogens to withstand lethal doses of structurally diverse drugs which are capable of eradicating non-resistant strains. MDR has been identified as a major threat to the public health of human being by the World Health Organization (WHO). Among the four general mechanisms that cause antibiotic resistance including target alteration, drug inactivation, decreased permeability and increased efflux, drug extrusion by the multidrug efflux pumps serves as an important mechanism of MDR. Efflux pumps not only can expel a broad range of antibiotics owing to their poly-substrate specificity of efflux pumps, but also drives the acquisition of additional resistance mechanisms by lowering intracellular antibiotic concentration and promoting mutation accumulation. Over-expression of multidrug efflux pumps have been increasingly found to be associated with clinically relevant drug resistance. On the other hand, accumulating evidence has suggested that efflux pumps also have physiological functions in bacteria and their expression is subject tight regulation in response to various of environmental and physiological signals. A comprehensive understanding of the mechanisms of drug extrusion, and regulation and physiological functions of efflux pumps is essential for the development of anti-resistance interventions. In this review, we summarize the development of these research areas in the recent decades and present the pharmacological exploitation of efflux pump inhibitors as a promising anti-drug resistance intervention.
    Biochemical and Biophysical Research Communications 05/2014; · 2.28 Impact Factor