期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 22, 页码 6344-6352出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.09.057
关键词
Thiadiazo; Dengue virus; NS2B/NS3
资金
- National Natural Science Foundation of China [81220108025, 21021063, 91229204, 81025017]
- National S&T Major Projects [2012ZX09103101-072, 2012ZX09301001-005, 2013ZX09507-001]
- Program of Shanghai Subject Chief Scientist [12XD1407100]
- Silver Project [260644]
Dengue virus is endemic throughout tropical and subtropical regions, and cause severe epidemic diseases. The NS2B/NS3 protease is a promising drug target for dengue virus. Herein, we report the discovery and modification of a novel class of thiadiazoloacrylamide derivatives with potent inhibitory activity against the NS2B/NS3 protease. Thiadiazolopyrimidinone 1 was firstly determined as a new chemical structure against NS2B/NS3 from a commercial compound library. Then, we sought to identify similar compounds with the thiadiazoloacrylamide core that would exhibit better activity. A series of analogues were synthesized and fourteen of them were identified with strong inhibitory activities, in which the nitrile group in the linker part was discovered as an essential group for the inhibitory activity. The best of these (8b) demonstrated an IC50 at 2.24 mu M based on in vitro DENV2 NS2B-NS3pro assays. (C) 2014 Published by Elsevier Ltd.
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