title: Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System.
abstract: Despite ongoing efforts, the available treatments for Chagas' disease are still unsatisfactory, especially in the chronic phase of the disease. Our previous study reported the strong trypanocidal activity of the dibenzylideneacetones A3K2A1 and A3K2A3 against Trypanosoma cruzi (Z. Ud Din, T. P. Fill, F. F. de Assis, D. Lazarin-Bidóia, V. Kaplum, F. P. Garcia, C. V. Nakamura, K. T. de Oliveira, and E. Rodrigues-Filho, Bioorg Med Chem 22:1121-1127, 2014, http://dx.doi.org/10.1016/j.bmc.2013.12.020). In the present study, we investigated the mechanisms of action of these compounds that are involved in parasite death. We showed that A3K2A1 and A3K2A3 induced oxidative stress in the three parasitic forms, especially trypomastigotes, reflected by an increase in oxidant species production and depletion of the endogenous antioxidant system. This oxidative imbalance culminated in damage in essential cell structures of T. cruzi, reflected by lipid peroxidation and DNA fragmentation. Consequently, A3K2A1 and A3K2A3 induced vital alterations in T. cruzi, leading to parasite death through the three pathways, apoptosis, autophagy, and necrosis.
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Lazarin-Bidóia
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Vânia Cristina
authors.initials: VC
authors.lastname: Desoti
authors.affiliation: Programa de Pós-graduação em Ciências Biológicas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Solange Cardoso
authors.initials: SC
authors.lastname: Martins
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Fabianne Martins
authors.initials: FM
authors.lastname: Ribeiro
authors.affiliation: LaBioMMi, Departamento de Química, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.
authors.forename: Zia
authors.initials: Z
authors.lastname: Ud Din
authors.affiliation: LaBioMMi, Departamento de Química, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.
authors.forename: Edson
authors.initials: E
authors.lastname: Rodrigues-Filho
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Tânia
authors.initials: T
authors.lastname: Ueda-Nakamura
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil Programa de Pós-graduação em Ciências Biológicas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Celso Vataru
authors.initials: CV
authors.lastname: Nakamura
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, Paraná, Brazil lautenschlager@uem.br.
authors.forename: Sueli
authors.initials: S
authors.lastname: de Oliveira Silva
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004847:Epithelial Cells / Q000469:parasitology; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D010422:Pentanones / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
chemical_list: C000611921:2-methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one; C000611920:2-methyl-1-(4-nitrophenyl)-5-phenylpenta-1,4-dien-3-one; D010422:Pentanones; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D014344:Trypanocidal Agents; D009569:Nitric Oxide