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

Autor: Oliveira-Tintino CDM; Laboratory of Pharmatoxicological Prospecting of Bioactive Products, Department of Antibiotics, Federal University of Pernambuco, UFPE, Recife, PE, Brazil., Tintino SR; Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Muniz DF; Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Rodrigues Dos Santos Barbosa C; Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Pereira RLS; Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Begnini IM; Department of Chemistry, Regional University of Blumenau, FURB, Itoupava Seca, 89030-903, Blumenau, SC, Brazil., Rebelo RA; Department of Chemistry, Regional University of Blumenau, FURB, Itoupava Seca, 89030-903, Blumenau, SC, Brazil., da Silva LE; Postgraduate Program in Sustainable Territorial Development, Coastal Sector, Federal University of Paraná, Curitiba, PR, Brazil., Mireski SL; Department of Chemistry, Regional University of Blumenau, FURB, Itoupava Seca, 89030-903, Blumenau, SC, Brazil., Nasato MC; Department of Chemistry, Regional University of Blumenau, FURB, Itoupava Seca, 89030-903, Blumenau, SC, Brazil., Krautler MIL; Department of Chemistry, Regional University of Blumenau, FURB, Itoupava Seca, 89030-903, Blumenau, SC, Brazil., Pereira PS; Laboratory of Pharmatoxicological Prospecting of Bioactive Products, Department of Antibiotics, Federal University of Pernambuco, UFPE, Recife, PE, Brazil., Balbino TCL; Department of Microbiology, Oswaldo Cruz Foundation, Aggeu Magalhães Research Center, CPqAM/Fiocruz, UFPE Campus, Recife, PE, Brazil., da Costa JGM; Laboratory of Natural Products, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Rodrigues FFG; Laboratory of Natural Products, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Teixeira AMR; Laboratory of Simulations and Molecular Spectroscopy, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Barreto HM; Laboratory of Microbiology, Federal University of Piaui, UFPI, Teresina, PI, Brazil., de Menezes IRA; Laboratory of Pharmacology and Molecular Chemistry, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil., Coutinho HDM; Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri, URCA, Crato, CE, Brazil. Electronic address: hdmcoutinho@gmail.com., da Silva TG; Laboratory of Pharmatoxicological Prospecting of Bioactive Products, Department of Antibiotics, Federal University of Pernambuco, UFPE, Recife, PE, Brazil.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2021 May 01; Vol. 160, pp. 105753. Date of Electronic Publication: 2021 Feb 10.
DOI: 10.1016/j.ejps.2021.105753
Abstrakt: 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.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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