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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Synthesis and Biological Evaluation of 2-Amino-1-phenyl-benzimidazole Derivatives as BACE1 Inhibitors

Author(s): Xiao-Bin Dai, Shi-Han Wu, Ning Ding, Yi-Yuan Ma, Zhen-Jiang Tong, Jia-Zhen Wu, Yi-Bo Wang, Yan-Cheng Yu, Xue-Jiao Leng, Xin Xue, Jin-Guo Xu, Wei-Chen Dai, Ke Xie, Jing-Han Zhao, Yu-Qi Hong, Tian-Xi Lan, Tian-Yu Mu, Xiao-Long Wang, Shan-Liang Sun*, Nian-Guang Li*, Qiao-Li Liang* and Liang Chang*

Volume 21, Issue 7, 2024

Published on: 15 March, 2023

Page: [1252 - 1262] Pages: 11

DOI: 10.2174/1570180820666230223151850

Price: $65

Abstract

Background: Alzheimer’s disease (AD), a chronic neurodegenerative disorder predominantly occurs among the elderly, is the leading cause of dementia. The accumulation of β-amyloid (Aβ) is considered the main pathogenies of AD, and β-site APP-cleaving enzyme 1 (BACE1) plays an important role in the formulation of Aβ.

Objective: In order to find a new scaffold as BACE1 inhibitors, a series of novel 2-amino-1-phenylbenzimidazole derivatives were designed and synthesized in this work.

Methods: Using our previous L-5 as a lead compound, we applied a scaffold hopping method and merged 2-amino-1-methyl-4-phenyl-1H-imidazol-5 (4H)-one into benzimidazole, so a novel class of BACE1 inhibitors T1~T20 with the structure of 2-amino-1-phenyl-benzimidazole were designed and synthesized.

Results: The biological activity evaluation indicated that the target compounds showed inhibitory activities against BACE1, with T14 being the most potent (IC50 = 0.45 μM), it also exhibited good logP value and tPSA. The docking studies indicated that compound T14 could form important hydrogen bonds with Asp289 and Asp93.

Conclusion: Compound T14 could be used as a potential BACE1 inhibitor for further modification to treat AD.

Keywords: Alzheimer's disease, BACE-1 inhibitor, benzimidazole derivatives, FRET, Compound T14, β-amyloid (Aβ).

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