Synthesis, structure–activity relationship studies using density functional theory and in silico molecular docking on substituted benzohydrazide derivatives

Abstract

The present study demonstrates the utility of benzohydrazide derivatives based on an approach to identify potential targets for a series of synthesized compounds that show potent anticancer activities against four cancer cell lines compared to other structurally related molecules. Benzohydrazide compounds have been synthesized effectively by the condensation of aldehyde and hydrazide at a 1:1 molar ratio. The complete series of compounds 1a-j were characterized by FT-IR, NMR, and one of them by single-crystal X-ray diffraction. The crystal structure of compound 1a shows a trans configuration around the CN bond and crystallized in a monoclinic system with C 2/c space group. All compounds exhibited good anticancer activity against four cancer cell lines such as A375 (human malignant melanoma), A549 (human lung adenocarcinoma), HT-29 (human epithelial intestinal) and MDA-MB-232(human metastatic breast). Among them, compound 1e shows the highest cytotoxic effect against the HT29 (IC50 = 0.47 µM) and A375 (IC50 = 0.80 µM) cell lines. Other compounds also exhibited promising anticancer activity. In addition, the nontoxic action was verified using the cytocompatibility assay on the L929 normal cell line and the hemolysis assay on human red blood cells. Parameters such as HOMO-LUMO energies, Hirshfeld surface analysis, and Molecular Electrostatic Potential (MEP) surface have been calculated using DFT and compared to experimental values of compounds 1a-c. In silico molecular docking studies revealed that the compound 1 h interacted very strongly with the 1T46 protein, with a docking score of −9.7 kcal/mol and very good binding via π–π, π-alkyl and π–σ interactions as compared to the standard drug. As a result of their potent cytotoxicity activities and computational analysis, these can be considered promising anticancer agents.