Design and Synthesis of Benzimidazole Derivatives as Anti-Cancer Agents

Abstract

Epidermal growth factor receptor (EGFR) is a member of the ErbB receptor tyrosine kinase receptor family and is highly expressed in solid tumours. It is one of the important targets in the development of the anticancer compound. Inhibiting EGFR is an important part of cancer treatment because it stops the growth and spread of tumour cells that express EGFR. Agents that target EGFR work well to treat many types of cancer, especially colorectal, head and neck, lung, liver, and breast cancers. In this study, the goal was to come up with some new benzimidazole compounds that can interact with the EGFR kinase enzyme, and evaluation of their biological activities in vitro was aimed. To get to the target compounds, 1-methyl-1H-benzimidazol-2-amine was made by cycloadding o-phenylenediamine with cyanogen bromide in the presence of an aqueous base like ammonium hydroxide. This was followed by N-methylation with methyl iodide in the presence of anhydrous potassium hydroxide in acetone. Benzimidazole urea derivatives were made by reacting methyl-amino benzimidazole derivatives with aryl isocyanates in the presence of DMSO and in an inert atmosphere. Twenty novel benzimidazole derivatives were obtained from series 1 and 2, and thirty,2-phenyl benzimidazole-based compounds were designed and synthesised using an accessible and cost-effective synthetic method as a result of this work. Element analysis, mass spectrometry, 1 H NMR spectroscopy, and 13C NMR spectroscopy, as well as HPLC analysis, all helped to elucidate the structures of these compounds. In-silico ADMET showed that the compounds made from benzimidazole, urea, and thiourea were safe and had properties like drugs. From all of this information, 50 compounds were chosen to be made and tested for their biological activity. Molecular docking studies have also been done on the synthesised compounds. Some molecules with high docking scores have been chosen and their ability to stop EGFR kinase has been tested. In an EGFR kinase assay, the compounds from Series 1, 2, and 3 (SRA1-20 and SRB11-40) with the highest docking scores were tested. Geftinib was used as a reference drug. The results showed that SRA01, with an IC50 of 0.93 . Between 6.8 - 37.5, other compounds had an inhibitory effect. MTT assays indicated that the compounds significantly inhibited the growth of both the HepG2 liver cancer cell line and the A549 lung cancer cell line. In an EGFR kinase assay, SRA1 and SRB27 were compared to Geftinib, the standard measure. For binding EGFR, SRA1 had the highest relative series affinity (IC50 = 0.98 nM), and it was also the most effective against both lung cancer cell lines (IC50 = 1.9 nM) and liver cancer cell lines (IC50 = 7.5 nM). In the cardiomyopathy experiment, chemical SRA1 produces no inflammatory or necrotic reactions, much as doxorubicin. Benzimidazole-linked urea molecules serve as a promising template for the design of new cancer treatments. Like the drug doxorubicin, the molecule does not trigger any inflammatory or necrotic reactions in the cardiomyopathy model. Through molecular docking, we find that this molecule has the lowest binding energy of the group. One should remember that benzimidazole-urea and thio urea derivatives serve as a useful template for the future discovery of more anticancer drugs.