合成香豆素-鸟苷缀合物抑制基孔肯雅病毒。
Chikungunya virus inhibition by synthetic coumarin-guanosine conjugates.
机构信息
Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan; Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 300, Taiwan; Department of Chemistry, National Central University, Jhongli City, Taoyuan, 320, Taiwan.
Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan; Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 300, Taiwan.
出版信息
Eur J Med Chem. 2019 Mar 15;166:136-143. doi: 10.1016/j.ejmech.2019.01.037. Epub 2019 Jan 21.
Since its discovery in Tanganyika, Africa in 1952, chikungunya virus (CHIKV) outbreaks have occurred in Africa, Asia, Europe, and America. Till now chikungunya fever has spread in nearly 40 countries. Because of lack of effective vaccines and antiviral drugs to intervene this disease, 21 new conjugated compounds were designed and synthesized by coupling of 6,8-dithioguanosine at its C-6 position with 3-(chloromethyl)coumarins bearing an F, Cl, Br, Me, or -OMe substituent through the -SCH- joint. Meanwhile, an organic "dummy" ligand (e.g., methyl, benzyl, and naphthylmethyl) or a coumarinyl moiety was attached at the C-8 position. By high through-put screening, three of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC = 9.9-13.9 μM) and showed low toxicity (CC = 96.5-212 μM). The selectivity index values were 9.37-21.7. Their structure-activity relationship was deduced, which indicates that the coumarin moiety is essential and the presence of a -OMe group enhances the antiviral activity.
自 1952 年在非洲坦桑尼亚发现以来，基孔肯雅病毒（CHIKV）已在非洲、亚洲、欧洲和美洲爆发。到目前为止，基孔肯雅热已传播到近 40 个国家。由于缺乏有效的疫苗和抗病毒药物来干预这种疾病，通过 -SCH- 键将 6,8-二硫代鸟苷在其 C-6 位置与带有 F、Cl、Br、Me 或 -OMe 取代基的 3-(氯甲基)香豆素偶联，设计并合成了 21 种新的共轭化合物。同时，在 C-8 位置连接了一个有机“虚拟”配体（如甲基、苄基和萘甲基）或香豆素部分。通过高通量筛选，发现其中三种新的缀合物在 Vero 细胞中对 CHIKV 具有显著的抑制作用（EC=9.9-13.9 μM），且毒性低（CC=96.5-212 μM）。选择性指数值为 9.37-21.7。推断了它们的构效关系，表明香豆素部分是必需的，-OMe 基团的存在增强了抗病毒活性。
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