Synthesis and molecular docking study of new thiazolidinones incorporating a benzoate moiety as anti-HepG2 cancer agents, EGFR inhibitors and apoptosis inducers

Abstract

Abstract Synthesis of new anticancer candidates with protein kinases inhibitory potency is a major goal of pharmaceutical science and synthetic research. This current work represents the synthesis of a series of substituted thiazolidinones incorporating a benzoate moiety, starting from 4-formylphenyl benzoate 1a and 4-formyl-2-methoxyphenyl benzoate 1b. Most prepared thiazolidinones 5a-j, 7a-h and 9a-j, were evaluated in vitro for their potential anticancer activity against three cell lines (HepG2, MCF-7 and HeLa). The most active cytotoxic compounds 3a, 3b, 5a, 5c and 5h were then further tested against the normal cell line WI38. All of these were shown be more effective toward anticancer cell lines. Thiazolidinones 5c and 5h were further evaluated to be kinase inhibitors against EGFR showing effective inhibitory impact. Furthermore, 5c and 5h were tested for their effects on cell cycle and apoptosis induction capability in HepG2 cell lines by DNA-flow cytometry analysis and annexin V-FITC apoptosis assay, respectively. The results showed that they have effect of disrupting the cell cycle and causing cell mortality by apoptosis in the treated cells. Moreover, molecular docking studies by the Moe 2015 program showed better binding patterns for 5c and 5hwith the active site of the EGFR protein kinase [PDB code 1M17]. Finally, toxicity risk and physicochemical characterization was performed for most of the compounds, revealing excellent properties as possible drugs, especially compounds 5c and 5h.