Identification of novel thiadiazoloacrylamide analogues as inhibitors of dengue-2 virus NS2B/NS3 protease |
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| Institution: | 1. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;2. School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, China;3. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;1. School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa;2. Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi 835215, India;1. Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA;2. Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA;1. Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India;2. Centre for Advanced Study in Crystallography and Biophysics, University of Madras, Chennai 600 025, Tamil Nadu, India |
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| 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 2.24 μM based on in vitro DENV2 NS2B-NS3pro assays. |
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| Keywords: | Thiadiazo Dengue virus NS2B/NS3 |
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