title: Imidazolium compounds are active against all stages of Trypanosoma cruzi.
abstract: Imidazolium salts are best known for their applications in organic synthesis as room-temperature ionic liquids, or as precursors of stable carbenes, but they also show important biological properties such as anti-oxidative effects, induction of mitochondrial membrane permeabilisation and inhibition of the infection cycle of Plasmodium falciparum. For these reasons, and since chemotherapy for Chagas disease is inefficient, the aim of this study was to test the use of imidazolium compounds against the kinetoplastid haemoflagellate aetiological agent for this disease, namely Trypanosoma cruzi. The results show that five of the tested compounds are more effective than the reference drug benznidazole against the epimastigote and trypomastigote forms of T. cruzi. Moreover, intracellular amastigotes were also affected by the compounds, which showed lower toxicity in host cells. Transmission electron microscopy analysis demonstrated that the tested agents induced alterations of the kinetoplast and particularly of the mitochondria, leading to extraordinary swelling of the organelle. These results further demonstrate that the test agents with the best profile are those bearing symmetrical bulky substituents at N(1) and N(3), displaying promising activity against all forms of T. cruzi, interesting selectivity indexes and exceptional activity at low doses. Accordingly, these agents represent promising candidates for the treatment of Chagas disease.
authors.affiliation: Unidad de Biología Molecular, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, Uruguay.
authors.forename: Paula
authors.initials: P
authors.lastname: Faral-Tello
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Liang
authors.affiliation: Cátedra de Química Farmacéutica, DQO, Facultad de Química, Universidad de la República, Avenida General Flores 2124, Montevideo, Uruguay.
authors.forename: Graciela
authors.initials: G
authors.lastname: Mahler
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Unidad de Biología Molecular, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2425, Montevideo, Uruguay. Electronic address: robello@pasteur.edu.uy.
authors.forename: Carlos
authors.initials: C
authors.lastname: Robello
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D000981:Antiprotozoal Agents; D007093:Imidazoles; D009593:Nitroimidazoles; C009999:benzonidazole
keywords: Chagas disease; Imidazolium derivatives; Trypanosoma cruzi