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

ABSTRACT

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.