5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms.

Oliver Orban (1) , Ricarda S Korn (1) , Diego Benítez (2) , Andrea Medeiros (2, 3) , Lutz Preu (1) , Nadège Loaëc (4) , Laurent Meijer (4) , Oliver Koch (5, 6) , Marcelo A Comini (2) , Conrad Kunick (1)

1 Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig]
2 Institut Pasteur de Montevideo
3 Departamento de Bioquímica, Facultad de Medicina
4 ManRos Therapeutics
5 Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
6 Faculty of Chemistry and Chemical Biology

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.

Mots clés: Trypanosoma brucei; Paullone; Neglected tropical diseases; Trypanosomiasis; Trypanothione synthetase; Leishmaniasis

Domaines: Sciences du Vivant [q-bio]; Microbiologie et Parasitologie

Oliver Orban, Ricarda S Korn, Diego Benítez, Andrea Medeiros, Lutz Preu, et al.. 5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms.. Bioorganic and Medicinal Chemistry, 2016, 24 (16), pp.3790-800. ⟨10.1016/j.bmc.2016.06.023⟩. ⟨pasteur-01499026⟩