Design, Synthesis, Biological Evaluation and Molecular Docking Study of New 1,3,4-Thiadiazole-Based Compounds as EGFR Inhibitors

Five series of new 1,3,4-thiadiazole hybrids were designed and synthesized as promising EGFR inhibitors. Three human Cancer cell lines were employed for testing each hybrid's in vitro antiproliferative efficacy; colon HCT-116, liver HepG-2 and breast MCF-7 using MTT assay. Comparing compound 9a to the reference doxorubicin, 9a shown superior activity to that of Dox with respect to MCF-7 (IC₅₀ 3.31 µM) while being secure for normal cells WI-38 (IC₅₀ = 43.99 µM). Further evaluation of the EGFR inhibitory activity of the most active candidates-4a, 6b, 8b, 9a, and 9 d-was performed. Of them, compounds 9a and 8b demonstrated the highest IC₅₀ values, 0.08 and 0.15 µM, respectively, relative to the reference gefitinib (IC₅₀ = 0.04 µM). Subsequent mechanistic analysis of compound 9a revealed a notable 14.24-fold increase in overall Apoptosis and a 28.92% cell cycle arrest at G2/M. Additionally, research on Apoptosis demonstrated that it triggered the mitochondrial apoptotic pathway. In MCF-7 cells, it also led to an increase in ROS buildup. For the most powerful EGFR inhibitors, 9a and 8b, a molecular docking research was conducted, and all of the findings agreed with the biological findings.

EGFR kinase; anticancer activity; docking studies; thiadiazole.