Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity
Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity
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DOI：
10.1016/j.ejmech.2017.06.015
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发表时间：
2017-09-29
影响因子：
6.7
通讯作者：
Tabarrini, Oriana
中科院分区：
文献类型：
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作者：
Desantis, Jenny;Nannetti, Giulio;Tabarrini, Oriana
为了寻找能够破坏流感病毒RNA依赖的RNA聚合酶PA-PB1亚基相互作用的小分子，本文在已有的结构和计算信息的基础上，设计并合成了一系列新的环七硫杂环-3-甲酰胺(CHTC)衍生物。它们的生物学评价突出了重要的结构见解以及新的有趣的化合物，如2-羟基苯甲酰胺衍生物29、31和32，以及4-氨基苯基衍生物54，它们在无毒浓度(CC50和GT；250亩M)下抑制低微摩尔范围内的病毒生长(EC50=0.18-1.2亩M)。这项研究允许获得PA-PB1相互作用抑制剂中最有效的抗流感化合物之一，证实cHTC支架特别适合实现创新的抗流感药物。(C)2017年爱思唯尔·马森公司。版权所有。
With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18 -1.2 mu M) at no toxic concentrations (CC50 > 250 mu M).This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents. (C) 2017 Elsevier Masson SAS. All rights reserved.