title: Identification of novel benzimidazole derivatives as anti-Trypanosoma cruzi agents: solid-phase synthesis, structure-activity relationships and molecular docking studies.
abstract: BACKGROUND
  In this paper, we report the solid-phase synthesis of 33 novel 1,2,5-tri-substituted benzimidazole derivatives and their in vitro activity on cruzipain and Trypanosoma cruzi epimastigotes.
  
  
  RESULTS
  Seven compounds were potent inhibitors of T. cruzi growth with IC50 values in the range 6-16 µM. Applying structure-activity relationships and principal component analysis strategies we were able to determine ring substituent effects and physicochemical properties that are important for the antichagasic activity of these novel derivatives, as well as get an insight into their possible mechanisms of action. Molecular docking studies revealed the binding orientation of the ligands in the active site of cruzipain providing new guidelines for the further design of better inhibitors.
  
  
  CONCLUSIONS
  Compound 2a constitute a promising hit compound for novel anti-T. cruzi agents showing that the benzimidazole scaffold may represent an interesting therapeutic alternative for the treatment of Chagas disease.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ríos
authors.forename: Javier
authors.initials: J
authors.lastname: Varela
authors.forename: Estefania
authors.initials: E
authors.lastname: Birriel
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Alicia
authors.initials: A
authors.lastname: Merlino
authors.forename: Williams
authors.initials: W
authors.lastname: Porcal
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D051379:Mice; D062105:Molecular Docking Simulation; D025341:Principal Component Analysis; D015800:Protozoan Proteins; D060327:Solid-Phase Synthesis Techniques; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C031000:benzimidazole; D003546:Cysteine Endopeptidases; C063214:cruzipain