Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives.

Ulviye Acar Cevik,Betul Kaya Cavuşoglu,Begüm Saglik,Derya Osmaniye,Yusuf Ozkay,Serkan Levent,Zafer Kaplancikli

doi:10.3390/molecules24050861

Ulviye Acar Cevik, Betul Kaya Cavuşoglu + Show 5 more

Open Access

https://doi.org/10.3390/molecules24050861

Copy DOI

Abstract

Alzheimer’s disease (AD), one of the main causes of aged dementia, is a progressive and degenerative neurological disorder characterized by loss of cognition and memory. Although the symptomatic treatment of AD, particularly acetylcholinesterase inhibitors (AChEIs) based on the ‘cholinergic hypothesis’, has been successful in clinic, at present there is no cure for this disease. In this study, we designed compounds carrying benzimidazole and triazole rings on the same chemical skeleton so as to investigate their potential acetylcholinesterase and butyrylcholinesterase activity. Furthermore, molecular modeling study was performed to determine the binding mode of the best inhibitor to the AChE. Among them, compounds 3d and 3h, which featured 3,4-dihydroxy substitution at the phenyl ring and 5(6)-chloro substitution at the benzimidazole ring were found to be potent inhibitors of AChE. The inhibition kinetics of the two most active derivatives 3d and 3h were further studied. The kinetic displayed increasing slope and increasing intercept, which is consistent with a mixed inhibition. The IC50 and Ki values of 3d are 31.9 ± 0.1 nM and 26.2 nM, respectively. Compound 3h exhibited IC50 of 29.5 ± 1.2 nM and Ki of 24.8 nM. The above data compared favorably with data for donepezil (21.8 ± 0.9 nM) the reference compound in our study.

Highlights

Neurodegeneration is defined as a progressive and often untreatable sequence that causes loss of specific neuron types, disregulation of neurons, distribution and central nervous system (CNS)dysfunction
Considering that there is a limited choice of medicines available for the treatment of Alzheimer’s disease (AD), we focused on using benzimidazole as a lead compound to develop new drug candidates to combat
AChE and BuChE are enzymes which play an important role in memory and cognition

Summary

Introduction

Neurodegeneration is defined as a progressive and often untreatable sequence that causes loss of specific neuron types, disregulation of neurons, distribution and central nervous system (CNS)dysfunction. Alzheimer’s disease (AD), which is one of the most important central nervous system disorders among various neurodegenerative diseases, is the fourth leading cause of death among the elderly. AD clinically includes the progressive degeneration of brain tissue that is influenced by the absence in acetylcholine (ACh) and has multifactorial pathology [1,2,3,4,5]. Accumulation of extracellular amyloid-beta (Aβ) in senile plaques, loss of cholinergic activity in certain parts of brain and intracellular neurofibrillary tangles including the hyperphosphorylated tau protein as well as neuroinflammation, responsible for neurodegenerative processes observed in AD [6,7,8]. The cholinergic hypothesis is one of the oldest, most robust and clinically confirmed among cases of mild severe dementia and Alzheimer’s hypotheses that suggest a relationship between the onset and progression of the disease.

Objectives

Methods

Results

Conclusion