期刊
CHEMMEDCHEM
卷 16, 期 19, 页码 3044-3059出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100282
关键词
medicinal chemistry; antibiotics; Staphylococcus aureus; NorA efflux pump inhibitors; quinazoline derivatives
资金
- MIUR-Ministero dell'Istruzione, dell'Universita e della Ricerca (Italian Ministry of Education, University and Research), PON R&I 2014-2020-AIM (Attraction and International Mobility) [AIM1873131-Num]
- [SA-1199]
- [SA-1199B]
- [SA-K1902]
- [SA-K2378]
The study developed pharmacophore models to identify NorA efflux pump inhibitors, with quinazoline core as the best performing scaffold. The synthesized 2-arylquinazolines demonstrated strong synergism with ciprofloxacin against resistant Staphylococcus aureus strains and low cytotoxicity against human cell lines, showing a promising safety profile.
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.
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