Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents

Yun-Xin Yao,Xiao-Xia Liang,Feng Gao,Xing-Xiu Chen,Nan-Nan Jia,Ya-Nan Cao

doi:10.3390/catal8100433

Abstract

2-aryl-N-alkylbenzimidazole derivatives synthesized by CuI/PPh3 promoted direct coupling of N-alkylbenzimidazoles with aryl bromides. In vitro neurotoxicities of 20 compounds were evaluated, and the neuroprotective abilities of low-neurotoxic compounds (3b, 3g, 3h, 3i, 3j, 3k, 3o, 3q, 3s and 3t) were investigated against toxicity induced by 1-methyl-4-phenylpyridinium ion (MPP+) in SH-SY5Y neuronal cells. In silico studies revealed that compound 3g could have molecule docking with the following proteins: the bone morphogenetic protein receptor type 1B (BMPR1B), human cytochrome P450 1B1(CYP1B1), Metabotropic glutamate receptor 7 (GRM7), histone deacetylase 6 (HDAC6), 5-hydroxytryptamine receptor 5A (HTR5A), human topoisomerase II beta (TOP2B). A molecular docking simulation of model compound 3g and model protein CYP1B1 has been shown.

Highlights

Benzimidazole derivatives are known to display a wide range of biological activities [1].Among them, the neuroprotective activity is significant in the treatment of neurodegenerative diseases including ischemia [2], epilepsy [3], and Alzheimer’s and Parkinson’s disease [4]
2-arylbenzimidazole derivatives were evaluated as inhibitors of c-Jun N-terminal kinase 3 (JNK3) in the treatment of neurodegenerative symptoms [6,7]
A novel cholinesterase (ChE) inhibitor with 2-arylbenzoimidazoles skeleton was helpful in reversing the memory impairments associated with Alzheimer’s disease [8]. 2-arylbenzimidazole derivatives inhibited the increase of inducible nitric oxide synthase when peripheral nerve injury occurred (Figure 1) [9]

Summary

Introduction

Benzimidazole derivatives are known to display a wide range of biological activities [1]. The neuroprotective activity is significant in the treatment of neurodegenerative diseases including ischemia [2], epilepsy [3], and Alzheimer’s and Parkinson’s disease [4]. Two clinically-promising anti-Parkinson’s disease agents, Istradefylline and Preladenant, are both benzimidazole derivatives [5]. 2-arylbenzimidazole derivatives were evaluated as inhibitors of c-Jun N-terminal kinase 3 (JNK3) in the treatment of neurodegenerative symptoms [6,7]. A novel cholinesterase (ChE) inhibitor with 2-arylbenzoimidazoles skeleton was helpful in reversing the memory impairments associated with Alzheimer’s disease [8]. There is a great demand for the generation a library of novel 2-arylbenzimidazoles for the evaluation of their neuroprotective activity

Methods

Results

Conclusion