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Chemical synthesis, molecular docking and MepA efflux pump inhibitory effect by 1,8-naphthyridines sulfonamides

2021; Elsevier BV; Volume: 160; Linguagem: Inglês

10.1016/j.ejps.2021.105753

1879-0720

Cícera Datiane de Morais Oliveira‐Tintino, Saulo Relison Tintino, Débora Feitosa Muniz, Cristina Rodrigues dos Santos Barbosa, Raimundo Luíz Silva Pereira, Iêda Maria Begnini, Ricardo Andrade Rebelo, Luiz Everson da Silva, Sandro Lucio Mireski, Michele Caroline Nasato, Maria Isabel Lacowicz Krautler, Pedro Silvino Pereira, Tereza Cristina Leal‐Balbino, José Galberto Martins da Costa, Fabíola Fernandes Galvão Rodrigues, Alexandre Magno Rodrigues Teixeira, Humberto Medeiros Barreto, Irwin Rose Alencar de Menezes, Henrique Douglas Melo Coutinho, Teresinha Gonçalves da Silva,

Quinazolinone synthesis and applications

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)-benzenesulfonamide (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)-benzenesulfonamide (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.