Synthesis, molecular docking, in silico ADME, and EGFR kinase inhibitor activity studies of some new benzimidazole derivatives bearing thiosemicarbazide, triazole, and thiadiazole

Abstract Epidermal growth factor receptor (EGFR), one of the important targets in the development of the anticancer compound, is a member of the ErbB receptor tyrosine kinase receptor family and is highly expressed in solid tumors. Inhibition of EGFR is important for cancer treatment to inhibit the progression and growth of EGFR‐expressing tumor cells. Agents targeting EGFR are successful drugs involved in the treatment of various cancers, particularly colorectal, head, neck, lung, and breast cancers. In this study, the design of some novel benzimidazole compounds that can interact with EGFR kinase enzyme, synthesis and analysis of these compounds, and evaluation of their biological activities in vitro was aimed. To reach the target compounds, by reacting acid hydrazides with alkyl isothiocyanates, thiosemicarbazides were formed, then cyclization of these compounds with concentrated sulfuric acid or sodium hydroxide, thiadiazole, or triazole derivatives were obtained. As a result of the study, a total of 38 new benzimidazole derivatives was obtained, and the structures of these compounds were clarified by elemental analysis, mass, 1 H, and 13 C NMR spectroscopy. Also, the structure of compound 4c was proven by X‐ray crystallography. Molecular docking studies of the synthesized compounds have also been carried out, some molecules with high docking scores have been selected and EGFR kinase inhibitor properties have been tested. Among the compounds tested, it was determined that the most active compound was 12a , which inhibited 68% EGFR at a concentration of 10 μM.