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

• Main Authors: Tommaso Felicetti, Gianmarco Mangiaterra, Rolando Cannalire, Nicholas Cedraro, Donatella Pietrella, Andrea Astolfi, Serena Massari, Oriana Tabarrini, Giuseppe Manfroni, Maria Letizia Barreca, Violetta Cecchetti, Francesca Biavasco, Stefano Sabatini
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: Journal of Enzyme Inhibition and Medicinal Chemistry
• Subjects: antimicrobial resistance breakers; efflux pump inhibitors; nora; staphylococcus aureus; antimicrobial resistance
• Online Access: http://dx.doi.org/10.1080/14756366.2020.1719083
• ISSN: 1475-6366; 1475-6374

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.