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
Dushyant V. Pathak, Jay B. Maheta, Darshna K. Lakhnotra, Yogesh O. Bhola, Hetali A. Modi, P. D. Suradiya, D. B. Chhag, Anil K. Mahida, Ghanshyam L. Jadav
Abstract
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.