Design, synthesis and biological evaluation of 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles as inhibitors of ebola virus infection
Design, synthesis and biological evaluation of 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles as inhibitors of ebola virus infection
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DOI：
10.1016/j.ejmech.2021.113211
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发表时间：
2021-02-03
影响因子：
6.7
通讯作者：
Agrofoglio, Luigi A.
中科院分区：
文献类型：
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作者：
Bessieres, Maxime;Plebanek, Elzbieta;Agrofoglio, Luigi A.
设计并合成了新型2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles作为埃博拉病毒的抑制剂。根据光谱数据和CHN分析，确定了新合成的苯并咪唑-哌啶杂化化合物的结构。对目标化合物进行了体外筛选，以确定它们的抗埃博拉活性。在被测分子中，化合物26a(EC(50=0.93µM，SI=10)和25a(EC_(50)=0.64µM，SI=20)对细胞的抑制作用与托瑞米芬参比药物(EC_(50)=0.38µM，SI=7)相当，而选择性更强。数据表明，25a和26a阻断EBOV感染的机制是通过在NPC1水平上抑制病毒进入。此外，对接研究表明，参与与GP结合的几个NPC1氨基酸参与了最活跃的化合物25a和26a的结合。最后，在计算机ADME预测中，26a是理想的类药物候选者。我们的结果可能使开发能够抑制埃博拉病毒的小分子药物成为可能，特别是在病毒进入阶段。(C)2021年爱思唯尔·马森公司。版权所有。
Novel 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles were designed and synthesized as Ebola virus inhibitors. The proposed structures of the new prepared benzimidazole-piperidine hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-Ebola activity. Among tested molecules, compounds 26a (EC(50=)0.93 mu M, SI = 10) and 25a (EC50= 0.64 mu M, SI = 20) were as potent as and more selective than Toremifene reference drug (EC50 = 0.38 mu M, SI = 7) against cell line. Data suggests that the mechanism by which 25a and 26a block EBOV infection is through the inhibition of viral entry at the level of NPC1. Furthermore, a docking study revealed that several of the NPC1 amino acids that participate in binding to GP are involved in the binding of the most active compounds 25a and 26a. Finally, in silico ADME prediction indicates that 26a is an idealy drug-like candidate. Our results could enable the development of small molecule drug capable of inhibiting Ebola virus, especially at the viral entry step. (C) 2021 Elsevier Masson SAS. All rights reserved.