Design, Synthesis, and Molecular Profiling of Pyrimidine‐Furan Derivatives Targeting EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S in NSCLC: In Vitro and In Silico Evaluation

Epidermal growth factor receptor (EGFR) mutations, especially in non‐small cell lung cancer (NSCLC), present significant challenges to targeted therapies due to acquired resistance. This study reports the synthesis and evaluation of a series of pyrimidine‐furan derivatives as potential anticancer agents. The compounds were screened using MTT and brine shrimp lethality assays, identifying R2, R10, and R12 as the most potent against NSCLC cell lines, particularly NCI‐H522 and NCI‐H1975. Compound R12 was most potent and selective against NCI‐H522, with an IC50 value of 0.95 ± .02 µM. EGFR inhibition assays confirmed R12 effectiveness with IC50 values of 1.62 ± 0.15 µM, 0.49 ± 0.23 µM, and 0.98 ± 0.02 µM against EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S, respectively. The compound R12 led to the cell cycle arrest in the G2/M and S phase of NCI‐H522 cells with an increase in apoptosis. Molecular docking and dynamics studies revealed strong binding affinity to EGFR (ΔG = ‐10.2 kcal/mol, Ki = 32.73 nM), stable protein‐ligand interactions. R12 also displayed antioxidant properties (DPPH IC50 = 12.11 ± 8.96 µM, H2O2 IC50 = 8.89 ± 1.72 µM). DFT and ADMET analysis predicted favorable pharmacokinetics, suggesting R12 potential as a promising lead for overcoming EGFR mutations, including triple mutations.