Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design,synthesis, and biological evaluation |
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| Institution: | 1. Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA;2. Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA;3. Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA;4. Department of Refractory Viral Infections, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan;5. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892, USA;6. Division of Clinical Sciences, Kumamoto University Hospital, Kumamoto 860-8556, Japan;1. Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic;2. Organic Research Laboratory, Department of Bioresources and Food Science, College of Life and Environmental Sciences, Konkuk University, Seoul 143 701, South Korea;1. European Institute for Molecular Imaging (EIMI), Waldeyerstr. 15, 48149, Münster, Germany;2. Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstr. 48, 48149, Münster, Germany;3. Leiden Academic Centre for Drug Research (LACDR), Leiden University, Division of Drug Discovery and Safety, Einsteinweg 55, 2333, CC Leiden, the Netherlands;4. Klinik für Neurologie Mit Institut für Translationale Neurologie, ICB, Mendelstr. 7, 48149, Münster, Germany;5. Institut für Physiologie I, Robert-Koch-Str. 27a, 48149, Münster, Germany;6. Oncode Institute, Leiden, the Netherlands;1. Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia;2. School of Pharmacy and Pharmacology, Griffith University, Gold Coast, QLD 4222, Australia;3. School of Chemistry, The University of Sydney, NSW 2006, Australia;4. Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia;1. Department of Parasitology, Instituto de Investigación Biosanitaria (ibs. Granada), Hospitales Universitarios de Granada/University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain;2. Department of Chemistry, Universitat de les Illes Balears, Ctra. Valldemossa, Km. 7.5, Palma 07122, Spain;3. School of Biosciences, University of Kent, Stacey Building, Canterbury CT2 7NJ, UK;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. Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium |
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| Abstract: | We describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing a squaramide-derived scaffold as the P2 ligand in combination with a (R)-hydroxyethylamine sulfonamide isostere. Inhibitor 3h with an N-methyl-3-(R)-aminotetrahydrofuranyl squaramide P2-ligand displayed an HIV-1 protease inhibitory Ki value of 0.51 nM. An energy minimized model of 3h revealed the major molecular interactions between HIV-1 protease active site and the tetrahydrofuranyl squaramide scaffold that may be responsible for its potent activity. |
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| Keywords: | HIV-1 protease Inhibitor Squaramide Synthesis |
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