title: Identification of novel thiadiazoloacrylamide analogues as inhibitors of dengue-2 virus NS2B/NS3 protease.
abstract: 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 2.24μM based on in vitro DENV2 NS2B-NS3pro assays.
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Ruoming
authors.initials: R
authors.lastname: Wu
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jingchen@simm.ac.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hliu@mail.shcnc.ac.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D020106:Acrylamide / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003716:Dengue Virus / Q000201:enzymology*; D007700:Kinetics; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000085242:Viral Proteases
chemical_list: D020106:Acrylamide; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D013830:Thiadiazoles; D017361:Viral Nonstructural Proteins; C079341:NS2A protein, Dengue virus type 2; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: Dengue virus; NS2B/NS3; Thiadiazo