Scuotto Maria, Abdelnabi Rana, Collarile Selene, Schiraldi Chiara, Delang Leen, Massa Antonio, Ferla Salvatore, Brancale Andrea, Leyssen Pieter, Neyts Johan, Filosa Rosanna
Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
Bioorg Med Chem. 2017 Jan 1;25(1):327-337. doi: 10.1016/j.bmc.2016.10.037. Epub 2016 Oct 31.
We recently identified indole derivatives (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities at lower micro molar concentrations and a selective index of inhibition higher than the lead compound Arbidol. Here we highlight new structural information for the optimization of the previously identified lead compounds that contain the indole chemical core. Based on the structural data, a series of indole derivatives was synthesized and tested for their antiviral activity against chikungunya virus in Vero cell culture by a CPE reduction assay. Systematic optimization of the lead compounds resulted in tert-butyl-5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)-indole-3-carboxylate derivative IIc with a 10-fold improved anti-CHIKV inhibitory activity (EC=6.5±1μM) as compared to Arbidol demonstrating a potent, selective and specific inhibition of CHIKV replication with only a moderate cell protective effect against other related alphaviruses. The reported computational insights, together with the accessible synthetic procedure, pave the road towards the design of novel synthetic derivatives with enhanced anti-viral activities.
我们最近鉴定出吲哚衍生物（IIIe和IIIf），其在较低微摩尔浓度下具有抗基孔肯雅病毒（CHIKV）的活性，且抑制选择性指数高于先导化合物阿比朵尔。在此，我们着重介绍新的结构信息，以优化先前鉴定出的含有吲哚化学核心的先导化合物。基于结构数据，合成了一系列吲哚衍生物，并通过CPE减少试验在Vero细胞培养物中测试其对基孔肯雅病毒的抗病毒活性。对先导化合物进行系统优化后得到了叔丁基-5-羟基-1-甲基-2-（2-三氟甲硫基）甲基）-吲哚-3-羧酸酯衍生物IIc，与阿比朵尔相比，其抗CHIKV抑制活性提高了10倍（EC = 6.5±1μM），证明其对CHIKV复制具有有效、选择性和特异性抑制作用，而对其他相关甲病毒只有适度的细胞保护作用。所报道的计算见解以及可行的合成方法，为设计具有增强抗病毒活性的新型合成衍生物铺平了道路。
