Title
From Quinoline to Quinazoline-Based S. aureus NorA Efflux Pump Inhibitors by Coupling a Focused Scaffold Hopping Approach and a Pharmacophore Search
Author
Nicholas Cedrato, Rolando Cannalire, Andreas Astolfi, Gianmarco Mangiaterra, Tommaso Felicetti, Salvatore Vaiasicca, Giada Cernicchi, Serena Massari, Giuseppe Manfroni, Oriana Tabarrini, Violetta Cecchetti, Maria Letizia Barreca, Francesca Biavasco, Stefano Sabatini
Year
2021
Journal
ChemMedChem
Abstract
Antibiotic resistance breakers, such as efflux pump inhibitors (EPIs), represent a powerful alternative to the development of new antimicrobials. Recently, by using previously described EPIs, we developed pharmacophore models able to identify inhibitors of NorA, the most studied efflux pump of Staphylococcus aureus. Herein we report the pharmacophore-based virtual screening of a library of new potential NorA EPIs generated by an in-silico scaffold hopping approach of the quinoline core. After chemical synthesis and biological evaluation of the best virtual hits, we found the quinazoline core as the best performing scaffold. Accordingly, we designed and synthesized a series of functionalized 2-arylquinazolines, which were further evaluated as NorA EPIs. Four of them exhibited a strong synergism with ciprofloxacin and a good inhibition of ethidium bromide efflux on resistant S. aureus strains coupled with low cytotoxicity against human cell lines, thus highlighting a promising safety profile.
Instrument
LC-4000
Keywords
antibiotic, antimicrobials, NorA, cytotoxicity