C-2 phenyl replacements to obtain potent quinoline-based NorA inhibitors.

NorA is the most studied efflux pump of and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative showed an improved EPI activity (16-fold) with respect to the starting hit . Moreover, compound exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (. Also, exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of "selectivity index" in comparison to .