New s ‐Triazine–Hydrazone Hybrids Targeting EGFR: Design and Anticancer Activity Against A549 Lung Adenocarcinoma

A new series of pyridine– s ‐triazine–hydrazone derivatives was designed, synthesized via an efficient two‐step route, and fully characterized by 1 H‐NMR, 13 C‐NMR, and elemental analyses. The compounds were evaluated for antiproliferative activity against A549 lung cancer cells and cytotoxicity toward WI‐38 fibroblasts. All derivatives showed measurable activity, with 6f and 6j exhibiting superior potency (IC 50 = 0.162 ± 0.01 and 0.152 ± 0.016 μm) compared with sorafenib (0.195 ± 0.02 μm), along with improved safety and selectivity indices. Both compounds also demonstrated strong antitrypsin activity, moderate Factor Xa inhibition, and enhanced EGF inhibitory effects relative to sorafenib. Molecular docking revealed binding scores of −6.856 to −4.812 and MM‐GBSA energies of −51.57 to −42.77 kcal/mol, exceeding those of sorafenib (docking score −4.805; ΔG‐bind = −35.02 kcal/mol). Docking analyses also indicated potential dual inhibition via interactions at the EGFR active site and MEK1 allosteric site, indicating stronger predicted EGFR binding affinities than sorafenib supporting a multitarget mechanism. Overall, 6f and 6j emerge as promising lead candidates for further development as dual EGFR/MEK inhibitors with additional protease‐modulating potential in NSCLC therapy.