Synthesis of Pyrido[2,3-d]Azolopyrimidinones: Design and Epidermal Growth Factor Receptor-Targeted Molecular Docking Toward Novel Anticancer Leads

A new class of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidinones and pyrido[2,3-d]thiazolo[3,2-a]pyrimidinones was synthesized by reacting 5-phenyl-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one with hydrazonoyl halides and α-bromoketones via a Knoevenagel-cyclocondensation followed by heteroannulation. Structures were confirmed by elemental analysis and IR, ¹H NMR, and MS spectroscopy. Cytotoxicity against HepG2 cells (MTT assay) revealed submicromolar activity for the most active analogs (IC₅₀ 0.72-0.95 µM), comparable to doxorubicin (0.65 µM). Structure-activity trends indicate that ester functionalities, coumarin incorporation, and electron-donating aryl substituents enhance potency. Molecular docking to the EGFR kinase domain showed strong predicted binding for the top analogs (scores -9.6 to -10.2 kcal mol^-1 vs -8.7 kcal mol^-1 for doxorubicin), highlighting key hydrogen-bond and hydrophobic contacts with Lys745, Asp837, Arg841, and Asp855. Docking results align with the in vitro data. In silico ADMET predictions suggest favorable drug-likeness, oral absorption, and non-mutagenic character. These findings position the reported pyridopyrimidine scaffolds as promising EGFR-targeted anticancer leads.