Synthesis, biological evaluation, molecular docking, molecular dynamics simulation, and ADME studies of novel...

A novel series of seven carbazole-aniline hybrids (5a-5 g) were designed, synthesized, and evaluated as potential anticancer agents. Among them, compound 5e, bearing a para-methoxy substituent, emerged as the most potent candidate, demonstrating significant cytotoxicity against breast cancer (MCF-7) and colon cancer (SW480) cell lines with IC₅₀ values of 26.4 ± 2.54 µM and 34.5 ± 1.69 µM, respectively. Notably, its activity against MCF-7 was comparable to the reference drug Erlotinib (IC₅₀ = 39.3 µM). Structure-activity relationship studies revealed that electron-donating groups significantly enhance cytotoxic effects, while electron-withdrawing substitutions diminish activity. Molecular docking studies showed that compound 5e binds effectively to the EGFR active site with a binding energy of -8.6 kcal/mol, forming key hydrogen bonds with critical residues Asp831 and Thr766. Molecular dynamics simulations further confirmed the stability of the 5e-EGFR complex. In silico ADME predictions indicated favorable drug-like properties for all compounds, consistent with Lipinski's Rule of Five. Based on its potent cytotoxicity, strong target binding, and optimal pharmacokinetic profile, compound 5e is identified as a promising lead candidate for further development as an EGFR-targeting anticancer agent.