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

ABSTRACT 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 (IC 50 3.31 µM) while being secure for normal cells WI‐38 (IC 50 = 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 IC 50 values, 0.08 and 0.15 µM, respectively, relative to the reference gefitinib (IC 50 = 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.