Design, Synthesis, and in Vitro Biological Evaluation of 1H-1,2,3-Triazole-4-carboxamide Derivatives as New Anti-influenza A Agents Targeting Virus Nucleoprotein

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• 作者：Huimin Cheng ; Junting Wan ; Meng-I Lin ; Yingxue Liu ; Xiaoyun Lu ; Jinsong Liu ; Yong Xu ; Jianxin Chen ; Zhengchao Tu ; Yih-Shyun E. Cheng ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2144-2153
• 全文大小：419K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

The influenza virus nucleoprotein (NP) is an emerging target for anti-influenza drug development. Nucleozin (1) and its closely related derivatives had been identified as NP inhibitors displaying anti-influenza activity. Utilizing 1 as a lead molecule, we successfully designed and synthesized a series of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents. One of the most potent compounds, 3b, inhibited the replication of various H3N2 and H1N1 influenza A virus strains with IC₅₀ values ranging from 0.5 to 4.6 渭M. Compound 3b also strongly inhibited the replication of H5N1 (RG14), amantidine-resistant A/WSN/33 (H1N1), and oseltamivir-resistant A/WSN/1933 (H1N1, 274Y) virus strains with IC₅₀ values in sub-渭M ranges. Further computational studies and mechanism investigation suggested that 3b might directly target influenza virus A nucleoprotein to inhibit its nuclear accumulation.