Novel Triazole-Urea Hybrids as Promising EGFR Inhibitors: Synthesis, Molecular Modeling and Antiproliferative Activity Studies Against Breast Cancer

Abstract

Breast cancer is the second leading cause of mortality among women globally. In this study, novel promising urea derivatives containing a 4-phenyl-5-sulphanylidene-4,5-dihydro-1H-1,2,4-triazole group were synthesized and evaluated for their biological activities against breast cancer. The cytotoxicity and apoptotic profiles of these compounds were assessed on the MCF7 breast cancer cell line and the L929 fibroblast cell line. Compound 5c exhibited the strongest anticancer activity against MCF7 cells with an IC50 value of 56.97±4.22 µM, while it showed significantly lower cytotoxicity against L929 cells (IC50 = 1651±18.39 µM). Compound 5c also induced early apoptosis in MCF7 cells, with an apoptosis rate of 18.40% and 5.28%, respectively. Additionally, the EGFR inhibitory activities of the synthesized compounds were evaluated, with compound 5i demonstrating the most potent EGFR inhibition, showing an IC50 value of 35.1 nM. These results suggest that compound 5c likely exerts its anticancer effects through mechanisms other than EGFR inhibition, while compound 5i has significant potential as an effective EGFR inhibitor. Molecular modeling studies were conducted to suggest putative binding interactions of compounds 5d, 5e and 5i with wildtype hEGFR. Further studies are warranted to explore their activity against other cancer types. © 2025 Elsevier B.V.