Design,synthesis and biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors |
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| Institution: | 1. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States;2. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, United States;3. Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States;1. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu 211800, China;2. Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA;1. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;2. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;4. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;1. Laboratorio de Química Medicinal, Centro de Investigaciones en Bionanociencias (CIBION)-CONICET, Godoy Cruz 2390, Ciudad de Buenos Aires, Argentina;2. Laboratory of Computational Chemistry and Drug Design, Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) – CONICET – Partner Institute of the Max Planck Society, Godoy Cruz 2390, Ciudad de Buenos Aires, Argentina;3. Instituto de Modelado e Innovación Tecnológica, CONICET, and Departamento de Fisica, FCENA-UNNE, Avda. Libertad 5460, Corrientes, Argentina;4. Fundación Instituto Leloir-CONICET, Av. Patricias Argentinas 435, Ciudad de Buenos Aires, Argentina;5. Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, CONICET, Av. 25 de Mayo y Francia, San Martín, Prov. de Buenos Aires, Argentina;1. Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;1. Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad 13100 AJK, Pakistan;2. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;3. Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792 Pakistan;4. Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan;1. KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium;2. KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium |
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| Abstract: | The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3?- or 5?-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para-position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to ?3 with nanomolar to low micromolar EC50 values. |
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| Keywords: | Dengue virus Spiropyrazolopyridone NS4B inhibitors Antiviral agents Structure-activity relationship (SAR) |
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