C-2 phenyl replacements to obtain potent quinoline-based <i>Staphylococcus aureus</i> NorA inhibitors

Abstract

NorA is the most studied efflux pump of <i>Staphylococcus aureus</i> 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 <b>37a</b> showed an improved EPI activity (16-fold) with respect to the starting hit <b>1</b>. Moreover, compound <b>37a</b> exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (<i>norA+)</i>. Also, <b>37a</b> exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of "selectivity index" in comparison to <b>1</b>.