Unveiling the potential anticancer activity of new dihydropyrimidines through dual inhibition of EGFR and TrkA: Design, synthesis, and in silico study.

Abstract

A series of designed scaffold of dihydropyrimidine was synthesized as dual tyrosine kinase targets inhibitors using a multicomponent Biginelli reaction which provided a high atom economy in a single pot reaction. Several 1,4-DHPM hybrids were obtained via alkylation with different chloroacetylamine derivatives. All the synthesized derivatives were screened for their antiproliferative efficacy towards various cancer cell lines (HCT-116, PC-3, and MCF-7) and normal cell line WI-38 using MTT assay. The results indicated that compounds 8h and 8i have the most significant inhibitory effect on all evaluated cancer cell lines, displaying IC50 of 3.94-15.78µM. Also, they demonstrated favorable selectivity towards normal cell lines. Moreover, the most active hybrids 8h and 8i were evaluated for their EGFR and TrkA inhibitory activity. The findings indicated that compound 8h had superior inhibitory activity compared to compound 8i on the targeted kinases, effectively stopping the G1 phase of the MCF-7 cell cycle and encouraging apoptosis. Additionally, the molecular docking studies declared that the most active compounds exhibited a notable binding interaction with the binding site of the target proteins. Furthermore, their physicochemical properties, ADMET profiles, and bioavailability radar plots were predicted and analyzed.