期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 23, 页码 9196-9213出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01047
关键词
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资金
- Agency for Science Technology and Research (A*STAR) [JCO 1231BFG046]
- National University of Singapore (NUS) [R-148-000-146-133]
Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus and is transmitted to humans by Aedes mosquitoes. Despite the re-emergence of CHIKV as an epidemic threat, there is no approved effective antiviral treatment currently available for CHIKV. Herein, we report the synthesis and structure activity relationship studies of a class of thieno [3,2-b]pyrroles and the discovery of a trisubstituted thieno[3,2-b]pyrrole 5-carboxamide 15c that exhibits potent inhibitory activity against in vitro CHIKV infection. Compound 15c displayed low micromolar activity (EC50 value of ca. 2 mu M) and limited cytotoxic liability (CC50 > 100 mu M) therefore furnishing a selectivity index of greater than 32. Notably, 15c not only controlled viral RNA production, but efficiently inhibited the expression of CHIKV nsP1, nsP3, capsid, and E2 proteins at a concentration as low as 2.5 mu M. More importantly, 15c also demonstrated broad spectrum antiviral activity against other clinically important alphaviruses such as O'nyong-nyong virus and Sindbis virus.
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