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

中文翻译：

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C-2苯基替代获得有效的基于喹啉的金黄色葡萄球菌NorA抑制剂。

NorA是金黄色葡萄球菌研究最多的外排泵，对氟喹诺酮类药物具有高水平耐药性。尽管多年来已经报道了许多NorA外排泵抑制剂（EPI），但关于其核周围的结构-活性关系（SAR）以及可靠的试验证明NorA抑制的数据的可靠性，目前尚缺乏足够的信息。在这方面，我们将精力集中在2-苯基喹啉上，将其作为开发有效的NorA EPI的有前途的化学型。在此，我们报告了有关在喹啉C-2位置引入不同芳基部分的SAR研究。新衍生物37a相对于起始命中1显示出提高的EPI活性（16倍）。此外，当化合物37a与环丙沙星组合使用抗SA-1199B（norA +）时，在时间杀灭曲线中显示出高潜力。也，