Integrated DFT, Molecular Docking, and In Silico ADME Analysis of New Benzimidazole Derivatives as Promising Anticancer Candidates Targeting MCF‐7 Cells

This study aims to synthesize new benzimidazole compounds and assess their anticancer potential in vitro using the human breast cancer cell line Michigan Cancer Foundation 7 (MCF-7). Using innovative molecular docking and computational analyses, this study investigates the therapeutic potential of newly synthesized benzimidazole derivatives by focusing on a protein that is strongly inhibited by doxorubicin, a widely used cancer treatment. Benzimidazole derivatives were synthesized via multiple approaches and were thoroughly characterized by Fourier transform infrared spectroscopy (FTIR) and ¹H NMR spectroscopy, as well as theoretical analyses. The results showed that Compounds A4 and A5 exhibited good potency against the tested breast cancer cell line, with IC₅₀ values of 142.6 and 187 µg/mL, respectively. Density functional theory (DFT) calculations were performed at the level to determine the most stable molecular conformation and its electrostatic and electronic properties. Molecular docking studies revealed that the effectiveness of Compounds (A1-A8) is comparable with that of doxorubicin (B), an FDA-approved anticancer molecule against estrogen receptor-α (ERα) protein, which is responsible for many side effects. The interaction of the A8 compound with protein 1A52 causes the best negative binding energy (-7.85 kcal/mol), whereas the calculated value for the B compound is -8.783 kcal/mol. Compounds (A1, A2, A3, A4, A5, A6, and A7) show a good binding energy for 1A52 (-5.41, -7.14, -6.29, -6.39, -6.65, -7.69, and -6.56 kcal/mol, respectively). Benzimidazole derivatives (A1-A8) may therefore be proposed as new anticancer agents targeting ERα protein.