Design, Synthesis, and Molecular Profiling of Pyrimidine-Furan Derivatives Targeting EGFR, EGFR, and EGFR 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 4-(2-substituted-6-(furan-2-yl)pyrimidin-4-yl)-substituted phenyl 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 IC value of 0.95 ± 0.02 µM as compared to standard afatinib (IC = 1.86 ± 0.22 µM). EGFR inhibition assays confirmed R12 effectiveness with IC values of 1.62 ± 0.15 µM, 0.49 ± 0.23 µM, and 0.98 ± 0.02 µM against EGFR, EGFR, and EGFR, 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 studies showed R12 high binding affinity (ΔG = -10.2 kcal/mol for EGFR; K = 32.73 nM) and significant interactions with key amino acids in the active site. Molecular dynamics simulations demonstrated stable protein-ligand interactions with low RMSD (0.17-0.27 nm) and significant eigenvalue (1.706 × 10). Compound R12 also exhibited antioxidant properties against DPPH (IC = 12.11 ± 8.96 µM) and HO (IC = 8.89 ± 1.72 µM). Furthermore, DFT analysis and ADMET predictions indicated that R12 possesses favorable physiochemical and pharmacokinetic properties, suggesting high bioavailability and minimal toxicity. These findings emphasize R12 as a promising lead for further preclinical investigation in overcoming EGFR mutations, including the challenging triple mutation.