Design, Synthesis, and Anticancer Evaluation of Novel Coumarin-1,3,4-Thiadiazole-Chalcone Hybrids as Dual EGFR/VEGFR2 Inhibitors: Molecular Docking, DFT, and ADMET Studies

Ten novel coumarine-1,3,4-thiadiazole-chalcone hybrid derivatives (8a-j) were synthesized via multistep synthesis and characterized by spectroscopic methods (IR,1H-NMR, mass spectrometry). Anticancer evaluation against MCF-7 and HepG2 cell lines revealed that compounds 8i (2-OCH3) and 8d (4-OCH3) exhibited potent cytotoxicity, with IC50 values of 13.2 ± 0.4 µM and 15.3 ± 0.6 µM, respectively, against MCF-7, superior to those of doxorubicin. SAR analysis indicated that ortho-methoxy substitution significantly enhanced anticancer potency. Molecular docking against EGFR (1M17) and VEGFR2 (3VHE) demonstrated strong binding affinities (−3.963 to −6.023 kcal/mol) through hydrogen bonds and π-π stacking interactions. DFT calculations of compound 8i revealed a HOMO-LUMO gap of 3.2008 eV and electrophilicity index of 5.8618 eV, supporting its reactivity and binding potential. ADMET profiling showed compounds 8a, 8c, 8d, 8h, and 8i possessed favorable drug-likeness (zero Lipinski violations), superior intestinal permeability (Caco-2: −4.84 to −4.91), and significantly reduced multi-organ toxicity compared to doxorubicin. These findings establish coumarine-1,3,4-thiadiazole-chalcone hybrids as promising anticancer scaffolds warranting further preclinical development.