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5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms
Institution:1. Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany;2. Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay;3. Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay;4. ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France;5. Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Straße 6, 44227 Dortmund, Germany;6. Technische Universität Braunschweig, Center of Pharmaceutical Engineering (PVZ), Franz-Liszt-Straße 35A, D-38106 Braunschweig, Germany;1. Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China;2. Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China;3. Lindsley F. Kimball Research Institute, New York Blood Center, NY 10065, USA;4. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan;1. Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA;1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China;2. Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China;3. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China;4. School of Life Science and Medicine, Dalian University of Technology, 2 Dagong Road, Panjin, China;1. Department of Chemistry, Hazara University, Mansehra 21120, Pakistan;2. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Department of Animal Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan;4. Department of Pharmacy, University of Lahore, Defence Road Campus, Lahore 53700, Pakistan;5. Department of Biochemistry, Hazara University, Mansehra 21120, Pakistan;6. Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;7. Rector Office, International Islamic University, Islamabad 44000, Pakistan;8. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;9. Pakistan Council for Science and Technology, G-5/2, Islamabad, Pakistan
Abstract:Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.
Keywords:Leishmaniasis  Neglected tropical diseases  Paullone  Trypanosomiasis  Trypanothione synthetase
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