Structural Modifications of the Quinolin-4-yloxy Core to Obtain New Staphylococcus aureus NorA Inhibitors

Abstract

Tackling antimicrobial resistance (AMR) represents a social responsibility aimed at renewing the antimicrobial armamentarium and identifying novel therapeutical approaches. Among the possible strategies, efflux pumps inhibition offers the advantage to contrast the resistance against all drugs which can be extruded. Efflux pump inhibitors (EPIs) are molecules devoid of any antimicrobial activity, but synergizing with pumps-substrate antibiotics. Herein, we performed an <i>in silico</i> scaffold hopping approach starting from quinolin-4-yloxy-based <i>Staphylococcus aureus</i> NorA EPIs by using previously built pharmacophore models for NorA inhibition activity. Four scaffolds were identified, synthesized, and modified with appropriate substituents to obtain new compounds, that were evaluated for their ability to inhibit NorA and synergize with the fluoroquinolone ciprofloxacin against resistant <i>S. aureus</i> strains. The two quinoline-4-carboxamide derivatives <b>3a</b> and <b>3b</b> showed the best results being synergic (4-fold MIC reduction) with ciprofloxacin at concentrations as low as 3.13 and 1.56 µg/mL, respectively, which were nontoxic for human THP-1 and A549 cells. The NorA inhibition was confirmed by SA-1199B ethidium bromide efflux and checkerboard assays against the isogenic pair SA-K2378 (<i>norA</i>++)/SA-K1902 (<i>norA</i>-). These <i>in vitro</i> results indicate the two compounds as valuable structures for designing novel <i>S. aureus</i> NorA inhibitors to be used in association with fluoroquinolones.