Novel 4-Anilinopyrimidine-N-Acylhydrazone derivatives as dual EGFRWT/VEGFR-2 tyrosine kinase inhibitors against non-small cell lung Cancer: Design, synthesis, biological evaluation, and computational studies.

Abstract

Two new series of 4-Anilinopyrimidine-N-acylhydrazone derivatives (7a-k and 9a-e) were designed and synthesized as potent dual EGFRWT/VEGFR-2 tyrosine kinase inhibitors. The in vitro antiproliferative activity of the compounds against MDA-MB-231, HepG2 and A549 cancer cell lines revealed derivatives 7e, 7i, 7k, 9a, and 9e were the most active, showing potent cytotoxicity against A549 NSCLC cells with IC50 values in the range of 1.25 to 7.20 μM compared to erlotinib (IC50 = 4.07 μM) and sorafenib (IC50 = 9.51 μM). Compound 9e was identified as the lead derivative with the most potent cytotoxicity against A549 cells (IC50 = 1.25 ± 0.11 μM), displaying 3.3- and 7.6-fold higher potency than erlotinib and sorafenib, respectively, with an excellent tumor selectivity over normal WI-38 fibroblasts (SI = 187.5). Enzyme inhibition assays confirmed potent dual kinase activity of 9e against EGFRWT (IC50 = 0.074 μM) and VEGFR-2 (IC50 = 0.055 μM) compared to erlotinib (EGFRWT IC50 = 0.043 μM) and sorafenib (VEGFR-2 IC50 = 0.098 μM). Annexin V-FITC/PI flow cytometry revealed apoptosis as the primary form of cell death in A549 cells induced by 9e. Molecular docking into EGFRWT and VEGFR-2 revealed that 9e reproduces the critical binding contacts of both reference inhibitors and forms additional unique interactions, rationalizing its superior potency. The molecular dynamics simulations demonstrated stable complex formation of 9e with both targets, with favorable MM-GBSA binding free energies of -26.23 and - 38.97 kcal/mol for EGFRWT and VEGFR-2, respectively.

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