Chiral 1,3,5‐Triazines as Potential EGFR Inhibitors: Pharmacophore Modeling, Synthesis, Molecular Docking, Molecular Dynamics Simulation, and Anticancer Evaluation

To target epidermal growth factor receptor (EGFR) signaling in breast (MCF-7) and lung (A549) cancers, a library of chirally functionalized 1,3,5-triazine scaffolds was designed by a ligand-based drug design approach. An optimized synthetic protocol employing sequential chlorine replacement on cyanuric chloride delivered enantiomerically pure chiral-1,3,5-triazine derivatives. Through systematic structural modifications, fine-tuned physicochemical properties and optimal ADME profiles are achieved. The synthesized compounds were evaluated for anticancer activity against MCF-7 (breast) and A549 (lung) cancer cell lines using the MTT assay. Molecular docking studies at the ATP-binding site of EGFR-TK demonstrate that compounds with the best docking score exhibit strong in vitro EGFR inhibitory activity, confirming a correlation between computational and experimental findings. A common pharmacophore hypothesis derived from established EGFR inhibitors enabled virtual screening of the synthesized library, yielding six top candidates. Among these, analogue (R)-4-((4-(3-methoxyphenoxy)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-yl)amino)benzonitrile (13c) exhibited the strongest cytotoxicity, with IC₅₀ values of 8.04 and 12.24 µM against MCF-7 and A549 cell lines, respectively. These results highlight chiral 1,3,5-triazines as promising leads for EGFR-targeted cancer therapy.