Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 5, Pages 2139-2150Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01803
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Funding
- NSFC [81573279, 81373255]
- Ministry of Education of China [313040]
- Hubei Province's Outstanding Medical Academic Leader Program
- Fundamental Research Funds for the Central Universities of China [2014306020201, 2042014kf10204]
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study
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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 SAP. led to potent enterovirus inhibitors, of which compound 15 exhibits significant improvements in inhibition potency with an EC50 value of 0.02 mu M 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 mu M and SI values in range of 978.4-12338. A preliminary mechanistic study indicated that VP1 might be the target site for this type of compound.
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