title: 5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms.
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.
authors.affiliation: Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany.
authors.forename: Oliver C F
authors.initials: OC
authors.lastname: Orban
authors.affiliation: Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany.
authors.forename: Ricarda S
authors.initials: RS
authors.lastname: Korn
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay.
authors.forename: Diego
authors.initials: D
authors.lastname: Benítez
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay.
authors.forename: Andrea
authors.initials: A
authors.lastname: Medeiros
authors.affiliation: Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Preu
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Koch
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay. Electronic address: mcomini@pasteur.edu.uy.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Comini
authors.affiliation: Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany; Technische Universität Braunschweig, Center of Pharmaceutical Engineering (PVZ), Franz-Liszt-Straße 35A, D-38106 Braunschweig, Germany. Electronic address: c.kunick@tu-braunschweig.de.
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
mesh_terms: D019732:Amide Synthases / Q000037:antagonists & inhibitors; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis / Q000379:methods; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D001552:Benzazepines; D007211:Indoles; C000621710:N-benzyl-2-(9-bromo-3-chloro-6-oxo-5,6,7,12-tetrahydrobenzo(2,3)azepino(4,5-b)indole-5-yl)acetamide; D019732:Amide Synthases; C064407:trypanothione synthetase
keywords: Leishmaniasis; Neglected tropical diseases; Paullone; Trypanosoma brucei; Trypanosomiasis; Trypanothione synthetase