Newly designed ۲-(aminomethyl)benzimidazole derivatives as possible tyrosine kinase inhibitors: synthesis, characterization, preliminary cytotoxic evaluation and in Silico studies

Benzimidazole is an isostere of purine nucleosides so; it is widely used as a basic nucleus in the development of different anticancer agents. Receptor tyrosine kinases (RTK) was found with high overexpression in many of aggressive cancer types. So, they are considered as important targets in cancer therapy. However, many of molecular mechanisms of resistance have been identified leading to multi-drug resistance thereby, as increase the need to discover new anticancer therapies. In this study, a set of ۲- (amino methyl) benzimidazole derivatives were designed and docked virtually then were synthesized, characterized and studied their preliminary structure-activity relationship for cytotoxic activities for two cancer cell lines (breast and lung cancer) as well as Vero normal cells, using gefitinib as a reference standard. Most of the synthesized compounds were active against T۴۷D cell line, and both ۴g and ۲g compounds give higher cytotoxicity than gefitinib, while A۵۴۹ cell line showed a highly resistance to all compounds even gefitinib. More interesting, all synthesized compounds were inactive against normal cells. The docking score results of the synthesized compounds were compatible to their cytotoxic activity, this evidence gives a good explanation that they could act as receptor tyrosine kinase inhibitors (RTKIs). ADME study of the highly cytotoxic compounds with gefitinib was done with good drug likeness and pharmacokinetic results.

کلیدواژه ها:

new benzimidazole derivatives ، tyrosine kinase inhibitors (TKIs) ، cytotoxic study ، docking study