title: Second generation of 2H-benzimidazole 1,3-dioxide derivatives as anti-trypanosomatid agents: synthesis, biological evaluation, and mode of action studies.
abstract: Exploring the influence of different substitution patterns of 2H-benzimidazole 1,3-dioxide derivatives (BzNO) we prepared fifteen new derivatives. Initially the BzNO were tested against Trypanosoma cruzi Tulahuen 2 strain epimastigote form rendering very potent anti-T. cruzi agents. Moreover, the BzNO were able to inhibit the growth of virulent and resistant to Benznidazole strains (CL Brener clone, Colombiana, and Y strains) and to Leishmania braziliensis. Interestingly, BzNO exhibited very high selectivity index and particularly the spiro-BzNO 13 provokes an important diminution of amastigotes in Vero cells. Besides, it was found a diminution of acetate and glycine as excreted metabolites but without increase of parasite glucose uptake indicating that the glycosome is probably not involucrate in the 2H-benzimidazole 1,3-dioxides mechanism of action.
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Igua 4225, 11400 Montevideo, Uruguay.
authors.forename: Mariana
authors.initials: M
authors.lastname: Boiani
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Alicia
authors.initials: A
authors.lastname: Merlino
authors.forename: Paola
authors.initials: P
authors.lastname: Hernández
authors.forename: Agustina
authors.initials: A
authors.lastname: Chidichimo
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cazzulo
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D007892:Leishmania braziliensis / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D014344:Trypanocidal Agents; C031000:benzimidazole; D010088:Oxidoreductases; D005947:Glucose