3-Arylpiperidines as potentiators of existing antibacterial agents

Important resistance patterns in Gram-negative pathogens include active eff lux of antibiotics out of the cell via, a cellular pump and decreased membr ane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC50 similar to 90 muM This report details the evaluation of the tether Length, aryl substitution and t he importance of the fluorine on antibiotic accumulation. Evaluation of var ious tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumul ation and the defluorinated analogue 17 is equally potent to the original l ead 1. (C) 2001 Elsevier Science Ltd. All rights reserved.