Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
Eur J Med Chem. 2017 Sep 29;138:128-139. doi: 10.1016/j.ejmech.2017.06.015. Epub 2017 Jun 8.
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 (EC = 0.18-1.2 μM) at no toxic concentrations (CC > 250 μM). 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.
为了寻找能够破坏流感病毒（flu）RNA 依赖性 RNA 聚合酶 PA-PB1 亚基相互作用的小分子，基于先前的结构和计算信息，本文设计并合成了一系列新型环己七硫酮-3-甲酰胺（cHTC）衍生物。通过对它们的生物学评估，我们发现了一些重要的结构见解，同时也得到了一些新的有趣的化合物，如 2-羟基苯甲酰胺衍生物 29、31 和 32，以及 4-氨基苯甲酰胺衍生物 54，它们在无毒性浓度（CC>250 μM）下以低微摩尔浓度（EC=0.18-1.2 μM）抑制病毒生长。这项研究获得了 PA-PB1 相互作用抑制剂中最有效的抗流感化合物之一，证实了 cHTC 支架特别适合开发创新型抗流感药物。
