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标题：Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents
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作者：Mai Ohba ; Tomoichiro Oka ; Takayuki Ando 等
期刊名称：Chemical and Pharmaceutical Bulletin
印刷版ISSN：0009-2363
电子版ISSN：1347-5223
出版年度：2016
卷号：64
期号：5
页码：465-475
DOI：10.1248/cpb.c16-00001
出版社：The Pharmaceutical Society of Japan
摘要：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 µM) 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 µM) and 4,6- di -fluoro-benzothiazole derivative 3j (EC₅₀=5.6 µM) 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 µM (70-fold more potent than 1 ). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.