In silico Design, Synthesis and Biological Evaluation of Novel Chalcone Derivatives as Potent Tubulin-Targeting Anticancer Agents

Tubulin is an essential protein involved in microtubule dynamics that regulate mitotic cell division in normal cells. Specifically, the colchicine-binding site of tubulin serves as a therapeutic target to disrupt microtubule dynamics, inducing mitotic arrest and leading to cell death. In current study, we synthesized methoxy and fluorine substituted novel chalcones (4a-o) and the synthesized chalcone compounds showed promising anticancer activity by in vitro cell viability using the MTT assay in the lung cancer (A549) and breast cancer (MCF-7) cell lines and in silico docking simulations along with optimization of drug-like and pharmacokinetic properties. Among all compounds, (E)-1-(4,6-dimethoxybenzofuran-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (4f) had the highest potency (IC50 = 23.9 ± 0.203 µM), followed by the fluorine substituted compound (E)-1-(4,6-dimethoxybenzofuran-2-yl)-3-(2,4,6-trifluorophenyl)prop-2-en-1-one (4m) (IC50 value of 35.44 µM). Moreover, compound 4f demonstrated an excellent docking interaction (-9.94 kcal/mol) with the key residues Met-259, Leu-255 and Ala-250 at colchicine-binding pocket of tubulin against millepachine, which is similar to the millepachine binding site of tubulin, suggesting a mechanism of action that may potentially affect microtubule dynamics. Additionally, compound 4f identified promising drug-like properties, physico-chemical and pharmacokinetic characteristics.