Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents
Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents
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DOI：
10.1248/cpb.c16-00001
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发表时间：
2016-05-01
影响因子：
1.7
通讯作者：
Asai, Akira
中科院分区：
文献类型：
--
作者：
Ohba, Mai;Oka, Tomoichiro;Asai, Akira
迫切需要结构新颖的抗诺罗病毒剂。在这项研究中，我们描述了一系列杂环甲酰胺衍生物的合成、抗诺如病毒活性和构效关系（SAR）。杂环甲酰胺 1（50% 有效浓度 (EC50)=37 mu M）是通过我们的筛选活动使用细胞病变效应减少测定法鉴定出来的。最初的 SAR 研究表明了杂环支架上卤素取代基的重要性，并确定了 3,5-二硼噻吩衍生物 2j (EC50=24 μM) 和 4,6-二氟苯并噻唑衍生物 3j (EC50=5.6 μM) 是比 1 更有效的抑制剂。此外，它们的杂化化合物 3,5-二溴噻吩-4,6-二氟苯并噻唑4b，显示出最有效的抗诺如病毒活性，EC50值为0.53μM（比1有效70倍）。进一步的研究表明4b可能抑制细胞内病毒复制或病毒感染的后期。
There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure-activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC50)=37 mu M) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC50=24 mu M) and 4,6-di-fluoro-benzothiazole derivative 3j (EC50=5.6 mu M) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC50 value of 0.53 mu M (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.