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Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold
Affiliation:1. Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Cairo, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Cairo, Egypt;3. Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Helwan, Cairo, Egypt;4. Basic and Applied Sciences Institute, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, 21934 Alexandria, Egypt;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia 11566, Cairo, Egypt;6. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China;2. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium;3. China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China;2. Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua 321004, China;1. Drug Design and Synthesis Lab, Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;2. Laboratory of Functional Genomics and Molecular Toxicology, CSIR-Central Drug Research Institute, (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031, India;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China;2. School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, 210009, Nanjing, PR China;3. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium;4. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, United States;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan;6. Surgical Science, Department of Surgery, Duke University Medical Center, Durham, NC, 27710, United States
Abstract:We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.
Keywords:HIV  LEDGF (lens epithelium-derived growth factor)  INLAIs (integrase-LEDGF/p75 allosteric inhibitors)
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