Rational Design, Synthesis, Biological Evaluation, and In Silico Study of N ‐Cinnamamide/Benzamide‐(4‐(Substituted Phenyl)‐6‐(4‐Cyclohexylphenyl)pyrimidin‐2‐Yl) Derivatives as EGFR Inhibitors Targeting EGFR WT , EGFR T790M , and EGFR L858R / T790M / C797S in NSCLC

Non‐small cell lung cancer (NSCLC), driven by mutations in the epidermal growth factor receptor (EGFR), presents significant therapeutic challenges, particularly due to drug resistance. This study describes the design, synthesis, and evaluation of a series of novel N ‐Cinnamamide/benzamide‐(4‐(substituted phenyl)‐6‐(4‐cyclohexylphenyl)pyrimidin‐2‐yl) derivatives ( Ri–Rxii ) as EGFR inhibitors. Among these, compound Riv exhibited superior antiproliferative activity against wild‐type and mutant EGFR‐driven NSCLC cell lines, including EGFR L858R/T790M and the drug‐resistant EGFR L858R/T790M/C797S variant, with low IC 50 values and minimal cytotoxicity towards normal cell lines. Compound Riv effectively induced cell cycle arrest at the S and G2/M phases and triggered apoptosis, with 54.38% of cells undergoing apoptotic or necrotic death. Additionally, Riv exhibited strong antioxidant activity, outperforming the standard ascorbic acid in DPPH and ABTS assays, indicating its ability to reduce oxidative stress. Molecular docking and dynamic simulation studies confirmed stable binding interactions with key EGFR residues, and DFT analysis revealed favorable electronic properties. Furthermore, in silico ADMET predictions highlighted Riv 's promising pharmacokinetic and toxicity profiles, supporting its potential as a safe and effective anticancer agent. This comprehensive evaluation positions Riv as a strong candidate for overcoming drug resistance in NSCLC treatment.