Design, Synthesis, in silico Study and Preliminary Cytotoxic Evaluation of New N-(Benzimidazol-2-yl-methyl) Benzamide Derivatives as Possible Tyrosine Kinase Inhibitors

Abstract

Receptor tyrosine kinases (RTKs) are expressed in high level in cancer cells making their targeting a justifiable strategy. Unfortunately, multiple molecular mechanisms of resistance had been identified, leading to drug resistance and toxicity, which increase the need to discover new structural tyrosine kinase inhibitors. In current study, a series of N-(benzimidazole-2-yl-methyl) benzamide derivatives were designed and docked virtually, then were synthesized, characterized, and studied preliminary structure-activity relationship for their cytotoxic activities against two cancer cell lines (breast, T47D, and lung cancer, A549) as well as Vero normal cells, using gefitinib as a reference standard. Then molecular dynamic simulation and ADME study for the most cytotoxic compound (4f) were done. According to the spectral analysis, all designed compounds were synthesized precisely. The cytotoxic studies revealed that most of the synthesized compounds were active against the T47D breast cancer cell line but felt beyond gefitinib, while only one compound (4f) was active against the A549 lung cancer cell line. More interestingly, all synthesized compounds were inactive against normal cells. Docking scores, molecular dynamic simulation as well as ADME studies of the compound (4f) gave good results. All these findings indicate that the compound (4f) is considered a good candidate for further pharmacological studies as a tyrosine kinase inhibitor (TKI).