title: In vivo anti-Chagas vinylthio-, vinylsulfinyl-, and vinylsulfonylbenzofuroxan derivatives.
abstract: New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias and Facultad de Química, Universidad de la República, Montevideo, Uruguay.
authors.forename: Williams
authors.initials: W
authors.lastname: Porcal
authors.forename: Paola
authors.initials: P
authors.lastname: Hernández
authors.forename: Mariana
authors.initials: M
authors.lastname: Boiani
authors.forename: Gabriela
authors.initials: G
authors.lastname: Aguirre
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Agustina
authors.initials: A
authors.lastname: Chidichimo
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cazzulo
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Campillo
authors.forename: Juan A
authors.initials: JA
authors.lastname: Paez
authors.forename: Ana
authors.initials: A
authors.lastname: Castro
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.forename: Carolina
authors.initials: C
authors.lastname: Davies
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Basombrío
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D015800:Protozoan Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010069:Oxadiazoles
chemical_list: D000913:Antibodies, Protozoan; D001583:Benzoxazoles; D003546:Cysteine Endopeptidases; D005978:Glutathione; D009247:NADH, NADPH Oxidoreductases; D015800:Protozoan Proteins; D013450:Sulfones; D014344:Trypanocidal Agents; D014753:Vinyl Compounds; C014354:benzofuroxan; D010069:Oxadiazoles; C049608:trypanothione reductase; C063214:cruzipain