Potent antiviral activity of novel multi-substituted 4-anilinoquin(az)olines |
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| Institution: | 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. Department of Chemistry, University of Patras, Patra, 26504, Greece;2. Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road 169857, Singapore;3. Institute for Glycomics, Griffith University, Gold Coast Campus, Australia;4. School of Biological Sciences, Nanyang Technological University, Singapore;5. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;6. Department of Pharmacy, University of Patras, Patras, 26504, Greece;1. Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, bus 1041, 3000, Leuven, Belgium;2. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA;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;1. Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University, Staudingerweg 5, 55128 Mainz, Germany;2. Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, University of Heidelberg, Im Neuenheimer Feld 344, 69120 Heidelberg, Germany;1. Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY 12208, USA;2. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA;3. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA;4. Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People''s Republic of China;5. Department of Biomedical Sciences, School of Public Health, University at Albany, PO Box 509, Empire State Plaza, Albany NY 12201, USA;1. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA;2. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA;3. Department of Bioengineering, Stanford University, Stanford, CA 94305, USA;4. Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA |
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| Abstract: | Screening a series of 4-anilinoquinolines and 4-anilinoquinazolines enabled identification of potent novel inhibitors of dengue virus (DENV). Preparation of focused 4-anilinoquinoline/quinazoline scaffold arrays led to the identification of a series of high potency 6-substituted bromine and iodine derivatives. The most potent compound 6-iodo-4-((3,4,5-trimethoxyphenyl)amino)quinoline-3-carbonitrile (47) inhibited DENV infection with an EC50 = 79 nM. Crucially, these compounds showed very limited toxicity with CC50 values >10 µM in almost all cases. This new promising series provides an anchor point for further development to optimize compound properties. |
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| Keywords: | Dengue Virus Flavivirus 4-Anilinoquinoline 4-Anilinoquinazoline Antiviral |
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