Identification of [1,2,3]Triazolo[4,5-d]pyrimidin-7(6H)-ones as Novel Inhibitors of Chikungunya Virus Replication

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• 作者：Alba Gigante ; Mar铆a-Dolores Canela ; Leen Delang ; Eva-Mar铆a Priego ; Mar铆a-Jos茅 Camarasa ; Gilles Querat ; Johan Neyts ; Pieter Leyssen ; Mar铆a-Jes煤s P茅rez-P茅rez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4000-4008
• 全文大小：355K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

Chikungunya virus (CHIKV) is a re-emerging Alphavirus that is transmitted to humans by Aedes mosquitoes. Currently, there are still no drugs or vaccines available for the treatment or prevention of this disease. Although traditionally restricted to Africa and Asia, the adaptation of the virus to Aedes albopictus, a mosquito species with an almost worldwide distribution, has contributed to the geographical spread of this virus in the past decade. Here, we report on a new family of compounds named [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones that inhibit CHIKV replication in the low micromolar range with no toxicity to the host (Vero) cells. The most potent compound in this series has an EC₅₀ value below 1 渭M with no cytotoxicity detected up to 668 渭M, therefore affording a selectivity index greater than 600. Interestingly, the compounds have little or no antiviral activity on the replication of other members of the Togaviridae family. The exploration and study of this class of selective inhibitors of CHIKV replication will contribute to deeper insights into the CHIKV life cycle and may be a first step toward the development of a clinical drug candidate.