title: Novel 3-nitro-1H-1,2,4-triazole-based compounds as potential anti-Chagasic drugs: in vivo studies.
abstract: BACKGROUND
  Chagas disease is caused by the parasite Trypanosoma cruzi, is endemic in Latin America and leads to an estimated 14,000 deaths per year and around 100 million people at risk of infection. Drugs currently used in the treatment of Chagas are old, partially effective and have numerous side effects.
  
  
  METHODS
  We have previously reported that 3-nitro-1H-1,2,4-triazole-based compounds demonstrate significant and selective activity against T. cruzi amastigotes in infected L6 cells via activation of a type I nitroreductase, specific to trypanosomatids. In the present work we evaluated in vivo 13 of these compounds based on their high in vitro potency against T. cruzi (IC50 < 1 µM) and selectivity (SI: toxicity to L6 cells/toxicity against T. cruzi amastigotes > 200). Representative compounds of different chemical classes were included. A fast luminescence assay with transgenic parasites that express luciferase, and live imaging techniques were used. A total of 11 out of 13 compounds demonstrated significant antichagasic activity when administered intraperitoneally for 5-10 days at relatively small doses. The best in vivo activity was demonstrated by amides and sulfonamide derivatives. ADMET studies were performed for specific compounds.
  
  
  CONCLUSIONS
  At least three compounds were identified as effective, non-toxic antichagasic agents suitable for further development.
authors.affiliation: NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
authors.forename: Howard S
authors.initials: HS
authors.lastname: Rosenzweig
authors.forename: Rachel
authors.initials: R
authors.lastname: Ashworth
authors.forename: Shane R
authors.initials: SR
authors.lastname: Wilkinson
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Grasiella
authors.initials: G
authors.lastname: Andriani
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D030781:Organisms, Genetically Modified; D021261:Parasitic Sensitivity Tests; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects; D015027:Zebrafish
chemical_list: D000577:Amides; D013449:Sulfonamides; D014230:Triazoles; D014344:Trypanocidal Agents; C045575:1,2,4-triazole