Design, synthesis, mechanistic evaluation, and in silico study of pyrimidine-coumarin hybrids as promising anticancer agents.

Breast and lung cancers remain among the leading causes of cancer-related mortality worldwide, highlighting the urgent need for the development of effective targeted therapeutics. In this study, a series of novel pyrimidine-coumarin hybrid derivatives were rationally designed, synthesized, and biologically evaluated for their antiproliferative activity against MDA-MB-231 breast cancer and A549 lung cancer cell lines. The synthesized compounds were initially screened using the MTT assay, followed by detailed mechanistic and computational investigations of the most active derivatives. Among the synthesized compounds, 8b exhibited the highest antiproliferative activity, with IC₅₀ values of 23.2 μM against MDA-MB-231 and 69.19 μM against A549 cells, while 8g displayed IC₅₀ values of 32.41 μM and 113.3 μM, respectively. Mechanistic studies revealed that compounds 8b and 8g significantly downregulated epidermal growth factor receptor (EGFR) protein, induced apoptosis, and triggered G2/M-phase cell-cycle arrest in MDA-MB-231 cells, suggesting that their antiproliferative effects are mediated through EGFR protein expression. Computational studies, including molecular docking, molecular dynamics simulations, MM/GBSA binding free-energy calculations, density functional theory (DFT) analysis, and ADMET prediction, provided complementary structural, energetic, electronic, pharmacokinetic, and drug-likeness insights into the observed biological activity by demonstrating stable binding of the lead compounds within the EGFR active site, together with favorable electronic, pharmacokinetic, and drug-likeness profiles. Collectively, these results identify pyrimidine-coumarin hybrids, particularly compounds 8b and 8g, as promising lead scaffolds for the development of EGFR-targeted anticancer agents against breast and lung cancers.