title: 2H-benzimidazole 1,3-dioxide derivatives: a new family of water-soluble anti-trypanosomatid agents.
abstract: Three series of benzimidazole N-oxide derivatives were developed and were examined for their activity against trypanosomatid parasites (Trypanosoma cruzi and Leishmania spp.). 2H-benzimidazole 1,3-dioxides displayed remarkable in vitro activities against both parasites, with derivatives 28, 29, and 32 being the most potent (IC50 < 5 microM) against the epimastigote form of T. cruzi and 28, 33, and 35 the most potent against the promastigote form of Leishmania spp. Unspecific cytotoxicity was evaluated using murine macrophages, and derivative 33 was not toxic at a concentration 30 times that of its IC50 against T. cruzi that was completely toxic for Leishmania spp., implying that the series of 2H-benzimidazole 1,3-dioxides is selective toward both trypanosomatid parasites. Derivatives 33 and 35 were submitted to an in vivo assay using an acute model of Chagas' disease and a short-term treatment (30 mg/kg/day orally administrated as aqueous solution, during 10 days). While in the control (untreated) and Benznidazole (50 mg/kg/day) groups survival fraction was 60.0% and 87.5%, respectively, none of the animals treated with derivatives 33 and 35 died. From the preliminary structure-activity relationship studies reduction potential and electrophilicity were found relevant to anti-T. cruzi activity. Active compounds are better electrophiles and more easily reduced than inactive ones.
authors.affiliation: Departamento de Química Organica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Uruguay.
authors.forename: Mariana
authors.initials: M
authors.lastname: Boiani
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Ana
authors.initials: A
authors.lastname: Denicola
authors.forename: Susana
authors.initials: S
authors.lastname: Torres de Ortiz
authors.forename: Elva
authors.initials: E
authors.lastname: Serna
authors.forename: Ninfa
authors.initials: N
authors.lastname: Vera de Bilbao
authors.forename: Luis
authors.initials: L
authors.lastname: Sanabria
authors.forename: Gloria
authors.initials: G
authors.lastname: Yaluff
authors.forename: Héctor
authors.initials: H
authors.lastname: Nakayama
authors.forename: Antonieta
authors.initials: A
authors.lastname: Rojas de Arias
authors.forename: Celeste
authors.initials: C
authors.lastname: Vega
authors.forename: Miriam
authors.initials: M
authors.lastname: Rolan
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gonzalez
mesh_terms: D000208:Acute Disease; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: C511634:2,2-dimethyl-5-(1,3-dioxolan-2-yl)-2H-benzimidazole; C511633:2,2-dimethyl-5-(hydroxyimino)methyl-2H-benzimidazole 1,3-dioxide; D001562:Benzimidazoles; D003497:Cyclic N-Oxides; D014344:Trypanocidal Agents