Urea and carbamate-functionalized quinazolin-2,4-dione derivatives as EGFR tyrosine kinase inhibitors: synthesis, anticancer evaluation, molecular docking and molecular dynamics studies.

Early epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated significant efficiency in the treatment of non-small cell lung cancer (NSCLC). The present study focuses on the design and synthesis of two novel classes of hybrid quinazolin-2,4-diones 2-17, privileged with urea and/or carbamate moieties, as EGFR-TK inhibitors. The first series was synthesized via Curtius rearrangement of acyl azide 1, affording the corresponding isocyanate intermediate, which was subsequently treated with various amines and/or water. On the other hand, the second series was obtained by treatment of compound 1 with different alcohols and/or phenols. The structures of all synthesized compounds were fully confirmed by elemental analysis and spectroscopic techniques. The antiproliferative activities were quantitively evaluated and compared with the reference drug afatinib across NCI-60 cell line panel. Notably, compounds 2b and 6a declared the highest antiproliferative activity. Overall, while compound 2b exhibited higher selectivity and potency against specific cell lines (notably NSCLC and CNS), compound 6a showed a broader and more consistent anticancer profile. In comparison with afatinib, both compounds exhibited promising growth inhibition, with 6a particularly demonstrating comparable or superior activity in selected ovarian cancer models. Molecular docking studies further supported these findings, revealing that compounds 2b (- 9.99 kcal/mol) and 6a (- 10.06 kcal/mol) have stronger binding affinities toward EGFR (PDB ID: 1XKK) than afatinib (- 9.8 kcal/mol). Molecular dynamics simulations and SASA calculations indicated that EGFR- 6a complex underwent an initial conformational fluctuation, with an RMSD peak of 3.6 Å at ~ 22 ns, followed by stabilization at an average RMSD of 2.25 ± 0.15 Å. In contrast, EGFR-2b complex showed superior stability, particularly after 30 ns, maintaining a lower steady-state RMSD of 2.10 ± 0.10 Å without major deviation events. Additionally, the semiempirical computations were achieved to investigate the structural confirmation and chemical reactivity behavior of the moieties. Pharmacokinetic parameters declared that compounds 2b and 6a, similar to afatinib, comply with Lipinski's rule without any violations. Overall, compounds 2b and 6a represent promising lead candidates for developing novel EGFR inhibitors for cancer treatment.