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

• Published in: European journal of pharmaceutical sciences 2021-05, Vol.160, p.105753-105753, Article 105753
• Main Authors: Oliveira-Tintino, Cícera Datiane de Morais, Tintino, Saulo Relison, Muniz, Débora Feitosa, Rodrigues dos Santos Barbosa, Cristina, Pereira, Raimundo Luiz Silva, Begnini, Iêda Maria, Rebelo, Ricardo Andrade, da Silva, Luiz Everson, Mireski, Sandro Lucio, Nasato, Michele Caroline, Krautler, Maria Isabel Lacowicz, Pereira, Pedro Silvino, Balbino, Tereza Cristina Leal, da Costa, José Galberto Martins, Rodrigues, Fabiola Fernandes Galvão, Teixeira, Alexandre Magno Rodrigues, Barreto, Humberto Medeiros, de Menezes, Irwin Rose Alencar, Coutinho, Henrique Douglas Melo, da Silva, Teresinha Gonçalves
• Format: Article
• Language: English
• Subjects: Antibacterial agent; Bacterial resistance; Ethidium bromide; Fluorescence; MepA efflux pump; SA-K2068
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2021.105753

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. [Display omitted]