[(Bromomethyl)phenyl]methyl-Conjugated Chalcone Derivatives as Potential Lung Cancer Inhibitors: Structure Modification, Molecular Docking, Molecular Dynamics and In Vitro Validation
Abstract
Chalcones from medicinal plants are attractive starting points for anticancer lead discovery, and this study aimed to improve the anti-NSCLC potential of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) from Syzygium nervosum through targeted structural modification and mechanistic computational analysis. Air-dried seeds were extracted with CH2Cl2, DMC was purified by silica gel chromatography and crystallization, and its structure was confirmed by HRMS, FTIR and NMR; 4'-O-derivatization with meta- or para-[(bromomethyl)phenyl]methyl groups afforded derivatives 2a and 2b (89-92% yield). Antiproliferative activity and cytotoxicity were evaluated by MTT assay in NSCLC cell lines (A549, NCI-H460) and normal lung fibroblasts (MRC-5) with osimertinib as a reference. Derivatives 2a and 2b showed enhanced activity against NCI-H460 (IC50 = 7.97 ± 0.62 µM and 7.91 ± 2.77 µM) while remaining weak against A549, and they were less cytotoxic to MRC-5 (IC50 ≥ 50 µM and 16.08 ± 0.45 µM) than osimertinib (IC50 = 3.43 ± 0.35 µM). DFT/MEP analyses, docking to wild-type EGFR (1M17; redocking RMSD 1.228 Å), and 500 ns × 3 replica MD simulations supported improved EGFR binding stability for 2a/2b, with MM/GBSA indicating favorable binding free energies (-28.78 ± 6.11 and -21.99 ± 9.39 kcal/mol). Overall, 4'-O-functionalization of DMC generated lead derivatives with improved in vitro activity in NCI-H460 and computationally supported target-ligand stabilization.
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