Identification and Structure–Activity Relationships of Diarylhydrazides as Novel Potent and Selective Human Enterovirus Inhibitors

详细信息    查看全文

• 作者：Xin Han ; Ningyuan Sun ; Haoming Wu ; Deyin Guo ; Po Tien ; Chune Dong ; Shuwen Wu ; Hai-Bing Zhou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：2139-2150
• 全文大小：633K
• ISSN：1520-4804

文摘

Enterovirus 71 (EV71) plays an important role in hand-foot-and-mouth disease. In this study, a series of diarylhydrazide analogues was synthesized, and the systematic exploration of SAR led to potent enterovirus inhibitors, of which compound 15 exhibits significant improvements in inhibition potency with an EC₅₀ value of 0.02 μM against EV71. It is very interesting that this class of diarylhydrazides exhibits activities against a series of human enteroviruses at the picomolar level, including EV71 and Coxsackieviruses B1 (CVB1), CVB2, CVB3, CVB4, CVB5, and CVB6 (EC₅₀ as low as 0.5 nM). Compared with the reference antienterovirus drug 1 (enviroxime) and known inhibitor 5 (WIN 51711), the four highly selective compounds 15, 27, 41 and 47 inhibited EV71 replication with EC₅₀ values of 0.17–0.02 μM and SI values in a range of 978.4–12338. A preliminary mechanistic study indicated that VP1 might be the target site for this type of compound.