Synthesis, biological investigation, and docking studies of benzimidazole derivatives as butyrylcholinesterase and acetylcholinesterase inhibitors

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Document Type : Original Article

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Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran

Abstract

The cholinergic hypothesis is one of the hypotheses of Alzheimer's disease that shows the relationship between the onset and progression of the disease. One of the main ways to increase the level of acetylcholine is to inhibit cholinesterase enzymes. The benzimidazole core is very important in medicinal chemistry research due to its high affinity to various enzymes and protein receptors. The present study was conducted in the synthesis of benzimidazole derivatives with the aim of investigating butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) inhibitory activity. In the first step of experimental study, the product 2-(chloromethyl)benzimidazole (2) was obtained, then the final three benzimidazole derivatives 3, 4, and 5 were synthesized from the reaction of 1 mmol 2-(Chloromethyl)benzimidazole and 1 mmol of piperazine, N-phenylpiperazine, and 2-phenylethan-1-amine, respectively. The structure of the prepared compounds was confirmed by 1H-NMR, 13C-NMR, and FT-IR spectroscopic methods. The ability of the compounds to inhibit AChE and BuChE was evaluated using Ellman’s assay. The results of this test showed the significant inhibitory activities of these compounds. Compound 5 with IC50 = 0.28 µM showed the highest inhibition against BuChE enzyme. The inhibitory activity of compound 5 against BuChE was better than donepezil. In addition, the interaction of compound 5, galantamine, and rivastigmine with BuChE enzyme was investigated using docking studies. In these studies, compound 5 with an energy value of -8.88 kcal/mol showed the best interaction with the active site of the receptor. According to the obtained results, compound 5 is the most promising compound for the development of benzimidazole derivatives against Alzheimer's disease.

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Applied Chemistry Today

Articles in Press, Accepted Manuscript
Available Online from 07 July 2024

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