Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C-Nucleosides as Favipiravir (T-705) Analogues

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• 作者：Guangyi Wang ; Jinqiao Wan ; Yujian Hu ; Xiangyang Wu ; Marija Prhavc ; Natalia Dyatkina ; Vivek K. Rajwanshi ; David B. Smith ; Andreas Jekle ; April Kinkade ; Julian A. Symons ; Zhinan Jin ; Jerome Deval ; Qingling Zhang ; Yuen Tam ; Sushmita Chanda ; Lawrence Blatt ; Leonid Beigelman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4611-4624
• 全文大小：612K
• 年卷期：0
• ISSN：1520-4804

文摘

Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a broad-spectrum antiviral agent, has shown potent anti-influenza activity in cell-based assays, and its riboside (2) triphosphate inhibited influenza polymerase. In one of our approaches to treat influenza infection, we designed, prepared, and tested a series of C-nucleoside analogues, which have an analogy to 2 and were expected to act by a similar antiviral mechanism as favipiravir. Compound 3c of this report exhibited potent inhibition of influenza virus replication in MDCK cells, and its triphosphate was a substrate of and demonstrated inhibitory activity against influenza A polymerase. Metabolites of 3c are also presented.