Abstract

Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-tri-O-acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC₅₀ (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC₅₀ = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC₅₀ = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).

Graphic abstract

中文翻译：

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1,2,3-三唑基核苷类似物的合成及其抗病毒活性。

摘要

基于在核苷类似物中寻找流感抗病毒药物很少引起化学家关注的事实，本研究报告了一系列 1,2,3-三唑基核苷类似物的合成，其中嘧啶片段与呋喃核糖基相连。 -1,2,3-triazol-4-yl 部分由可变长度的聚亚甲基接头组成。通过 Cu 炔烃-叠氮化物环加成 (CuAAC) 反应制备目标化合物。尿嘧啶、6-甲基尿嘧啶、3,6-二甲基尿嘧啶、胸腺嘧啶和喹唑啉-2,4-二酮的衍生物，在N 1 (或N 5) 原子上具有 ω-炔烃取代基和叠氮基 2,3,5-三-O-乙酰基-D-β-呋喃核糖苷用作CuAAC反应的组分。评估了所有合成的化合物对流感病毒 A/PR/8/34/(H1N1) 和柯萨奇病毒 B3 的抗病毒活性。_{IC 50}（抑制浓度）和 SI（选择性指数）的最佳值由先导化合物4i证明，其中 1,2,3-三唑基呋喃核糖基片段连接到quinazoline-2,4-dione的N 1 原子通过丁烯接头 (IC ₅₀  = 30 μM, SI = 24) 和化合物8n，其中 1,2,3-三唑基呋喃核糖基片段直接连接到6-甲基尿嘧啶部分的N 5 原子上 (IC ₅₀ = 15 μM，SI = 5)。根据理论计算，1,2,3-三唑基核苷类似物4i和8n对 H1N1 (A/PR/8/34) 流感病毒的抗病毒活性可以通过它们对聚合酶酸性蛋白功能的影响来解释。 PA) 的 RNA 依赖性 RNA 聚合酶 (RdRP)。

图形摘要