NOVEL IMIDAZOLE CONTAINING CHALCONE DERIVATIVES AS AN AROMATASE INHIBITOR: SYNTHESIS, DOCKING STUDIES, BIOLOGICAL SCREENING AND ADME STUDIES

Abstract

Chalcone derivatives have been proven and documented as non-steroidal anticancer agents. A study of chalcone can be performed as an aromatase inhibitor. One crucial strategy for managing estrogen-positive breast cancer is aromatase inhibition. A total of 13 derivatives of chalcone were synthesized by the aldol condensation reaction and characterized by FTIR, MS, and NMR. Molecular docking was performed by the maestro Schrodinger Suite. In silico ADME study was executed by the QikProp software. All 13 compounds were assessed for the cytotoxicity study in human cancer cell line MCF-7 and are subject to further aromatase inhibition assay on selected chalcone derivatives. Four compounds, 3gA, 3jA, 3kA, and 3lA were found to be more potent chalcone derivatives with their IC50 values of 18.13±1.19 µM, 21.71±1.61 µM, 16.36±1.47 µM and 21.06±1.87 µM, respectively. Using a fluorogenic test kit, the in vitro aromatase inhibitory activity of four drugs (3gA, 3jA, 3kA, and 3lA) was investigated. The values of IC50 for compounds 3gA, 3jA, 3kA, and 3lA were found to be 2.76±0.83 µM, 6.45±3.38 µM, 4.82±1.52 µM and 3.00±1.63 µM, respectively. Lastly, QikProp 4.8 software was used to calculate the ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds. It was concluded that 3gA is the most potent compound having potent aromatase inhibitory activity in comparison to Letrozole with an IC50 value of 2.76±0.83 µM. At the same time, 3jA and 3lA have good aromatase inhibitory activity. Therefore, For the identification of aromatase inhibitory activity, these compounds make good lead compounds for further study as anticancer agents.