期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 160, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejps.2021.105753
关键词
Antibacterial agent; Bacterial resistance; Ethidium bromide; Fluorescence; SA-K2068; MepA efflux pump
资金
- Foundation for Support of Science and Technology of the State of Pernambuco (FACEPE) [IBPG-1241-4.03/16]
- National Council of Scientific and Technological Development (CNPq) [150456/2018-2, 406685/2018-5]
- Coordination for the Improvement of Higher Education Personnel (CAPES) [001]
- Financier of Studies and Projects (FINEP)
This study evaluated the antibacterial activity and inhibition of efflux mechanisms of a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The synthesized compounds showed no antibacterial activity but exhibited a favorable pharmacokinetic profile and potential inhibitory action on the MepA efflux pump, as demonstrated in molecular docking studies.
This study aimed to evaluate the antibacterial activity and to verify, in silico and in vitro, the inhibition of efflux mechanisms using a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The chemical synthesis occurred through the thermolysis of the Meldrum?s acid adduct. The sulfonamide derivatives were obtained by the sulfonylation of 2-amino-5-chloro-1,8-naphthyridine with commercial benzenesulfonyl chloride. Antibacterial activity was assessed by the broth microdilution test. Efflux pump inhibitory capacity was evaluated in silico by molecular docking and in vitro by analyzing synergistic effects on ciprofloxacin and ethidium bromide (EtBr) and by EtBr fluorescence emission assays. The following 1,8-naphthyridines were synthesized: 4-methyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfona-mide (Compound 10a); 2,5-dichloro-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10b); 4-fluoro-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10c); 2,3,4-trifluoro-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10d); 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10e); 4-bromo-2,5-difluoro-N-(5-chloro-1,8-naphthyridin-2-yl)-benzene-sulfonamide (Compound 10f). The 1,8-naphthyridines derivatives associated with sulfonamides did not show antibacterial activity. However, they showed a favorable pharmacokinetic profile with possible MepA efflux pump inhibitory action, demonstrated in molecular docking. In addition to the promising results in reducing the concentration of intracellular EtBr. 1,8-naphthyridines act as putative agents in the inhibitory action of the MepA efflux pump.
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