Chemical synthesis, molecular docking and MepA efflux pump inhibitory effect by 1,8-naphthyridines sulfonamides
| Autor: | Raimundo Luiz Silva Pereira, Michele Caroline Nasato, Irwin Rose Alencar de Menezes, Débora Feitosa Muniz, José Galberto Martins da Costa, Pedro Silvino Pereira, Fabíola Fernandes Galvão Rodrigues, Maria Isabel Lacowicz Krautler, Iêda Maria Begnini, Tereza Cristina Leal Balbino, Humberto Medeiros Barreto, Luiz Everson da Silva, Cícera Datiane de Morais Oliveira-Tintino, Teresinha Gonçalves da Silva, Saulo R. Tintino, Henrique Douglas Melo Coutinho, Cristina Rodrigues dos Santos Barbosa, Ricardo Andrade Rebelo, Alexandre Magno Rodrigues Teixeira, Sandro Lucio Mireski |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmaceutical Science
Microbial Sensitivity Tests 02 engineering and technology 030226 pharmacology & pharmacy Chemical synthesis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Bacterial Proteins medicine Naphthyridines Antibacterial agent Sulfonamides Chemistry Sulfonamide (medicine) 021001 nanoscience & nanotechnology Combinatorial chemistry In vitro Anti-Bacterial Agents Molecular Docking Simulation Benzenesulfonyl chloride Efflux Multidrug Resistance-Associated Proteins 0210 nano-technology Antibacterial activity Ethidium bromide medicine.drug |
| Zdroj: | European Journal of Pharmaceutical Sciences. 160:105753 |
| ISSN: | 0928-0987 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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