Synthesis, In Vitro Evaluation, and Molecular Docking Studies of Novel 3,5-Diphenyl-1H-1,2,4-Triazole Derivatives as Potential hEGFR Inhibitors

Abstract

EGFR, an important target in cancer chemotherapy, is an important component of the signaling system that regulates important cellular processes such as growth, differentiation, metabolism, and apoptosis in response to both internal and external stimuli. Based on this approach, comprehensive modeling studies targeting the EGFR protein were performed, and synthesized molecules were proposed. For this purpose, the synthesis of new 3,5-diphenyl-1H-1,2,4-triazole derivatives containing semicarbazide, thiosemicarbazide, 1,2,4-triazole-3-thione, and 1,2,4-triazole-3-one units was carried out. Among these compounds, 6a-6i presented in the present study exhibited EGFR inhibition in the nanomolar range. In addition, molecules 5e and 6e showed significant IC₅₀ values. Compound 6e showed the closest IC₅₀ value to gefitinib, a well-known EGFR inhibitor, with its noncompetitive inhibition mode. The K_i value of compound 6e was determined as 0.174 µM.

Keywords: 3,5‐diphenyl‐1H‐1,2,4‐triazole; docking; hEGFR; molecular modeling; semicarbazide; thiosemicarbazides.