Síntese, estudos in silico e avaliação da atividade anticâncer e antimicrobiana de novas chalconas produzidas a partir da 1,2-difenil-etanodiana

Abstract

Chalcones are compounds with two aromatic rings connected by three carbon atoms in an α,β-unsaturated ketone. They are used as therapeutic alternatives for various diseases and synthesized through a ketone and an aldehyde. However, conventional syntheses have synthetic disadvantages and low yield. For this reason, the work focuses on obtaining this class through a new synthetic route, and from this, the antibacterial and anticancer activities of the products obtained are investigated, in addition to carrying out molecular docking studies to evaluate their mechanisms of action. The synthesis was promoted by the combination of acetophenones + benzyl, by basic catalysis, through mechanochemistry, and the reaction products were characterized by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The antibacterial activity was performed against E. Coli, S. Aureus, P. Aeruginosa and E. Faecalis by plate microdilution and the cytotoxic activity was evaluated against tumor cell lines of MCF-7 (breast adenocarcinoma), HeLa (epithelial carcinoma of the cervix uterine) and PC-3 (prostate adenocarcinoma) by MTT assay. Molecular docking studies were performed using the AutoDockTools program version 1.5.6 for four proteins related to antibacterial activity (2EX6, 4URN, 3FRE and 3MTE) and three proteins for evaluation of anticancer activity (4Y72, 1HVY and 5GWK) with different mechanisms of action. The three synthesized molecules exhibited interesting yields ranging from 60-94%. NMR spectra allowed the identification of three chalcones: 1,2,4-triphenyl-2-buten-1,4-dione (CH-01), 4-(3-methoxyphenyl)-1,2-diphenyl-2 -buten-1,4-dione (CH-02), 4-(3-methylphenyl)-1,2-diphenyl-2-buten-1,4-dione (CH-03), with CH-02 being once described in the literature. Docking showed promising results, with CH-02 and CH-03 being the most promising molecules for all targets, especially 3FRE with ΔG results ranging from -10.43 to -10.45 Kcal.mol-1; and 4Y72, providing values from -10.99 to -11.17 Kcal.mol-1. CH-02 and CH-03 chalcones showed moderate antibacterial activity, with a MIC of 512 µg.mL-1 for the S. aureus strain. The three chalcones showed moderate cytotoxic activity against HeLa and MCF-7 cells, with CH-01 being the one that showed reduced cell viability for both strains.