Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole
Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole
复制标题
DOI：
10.1016/j.bmcl.2012.11.095
复制
发表时间：
2013-02-01
影响因子：
2.7
通讯作者：
Hruby, Dennis E.
中科院分区：
文献类型：
--
作者：
Dai, Dongcheng;Burgeson, James R.;Hruby, Dennis E.
筛选约400，000个小分子的化学多样性文库的抗慢病毒假型的抗病毒活性，其中掺入了拉沙病毒包膜糖蛋白（LASV GP）基因。高通量筛选导致发现具有苯并咪唑核心的命中化合物（ST-37），其导致有效的化合物系列。在此，我们报告SAR研究，其中涉及的苯环和连接到苯并咪唑核心的甲氨基接头部分的结构修饰。本研究中的许多类似物对LASV假型具有个位数纳摩尔效力。该苯并咪唑系列中的化合物还表现出针对由其他沙粒病毒包膜产生的假型的纳摩尔级抗病毒活性，表明开发广谱抑制剂的潜力。最终，鉴定了先导化合物ST-193，随后发现其在致死性LASV豚鼠模型中有效，与利巴韦林治疗相比显示出上级保护作用。(c)2012爱思唯尔有限公司保留所有权利。
A chemically diverse library of about 400,000 small molecules was screened for antiviral activity against lentiviral pseudotypes with the Lassa virus envelope glycoprotein (LASV GP) gene incorporated. High-throughput screening resulted in discovery of a hit compound (ST-37) possessing a benzimidazole core which led to a potent compound series. Herein, we report SAR studies which involved structural modifications to the phenyl rings and methylamino linker portion attached to the benzimidazole core. Many analogs in this study possessed single digit nanomolar potency against LASV pseudotypes. Compounds in this benzimidazole series also exhibited nanomolar antiviral activity against pseudotypes generated from other arenavirus envelopes indicating the potential for development of a broad-spectrum inhibitor. Ultimately, lead compound ST-193 was identified and later found to be efficacious in a lethal LASV guinea pig model showing superior protection compared to ribavirin treatment. (c) 2012 Elsevier Ltd. All rights reserved.