Author | Bastos, Tanira Matutino | |
Author | Barbosa, Marília Imaculada Frazão | |
Author | Silva, Monize Martins da | |
Author | José Júnior, W. da C | |
Author | Meira, Cássio Santana | |
Author | Guimarães, Elisalva Teixeira | |
Author | Ellena, Javier Alcides | |
Author | Moreira, Diogo Rodrigo Magalhães | |
Author | Batista, Alzir Azevedo | |
Author | Soares, Milena Botelho Pereira | |
Access date | 2014-09-15T17:29:28Z | |
Available date | 2014-09-15T17:29:28Z | |
Document date | 2014 | |
Citation | BASTOS, T. M. et al. Nitro/nitrosyl ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death. Antimicrobial Agents Chemotherapy, p.1-42, agos. 2014. | pt_BR |
ISSN | 0066-4804 | |
URI | https://www.arca.fiocruz.br/handle/icict/8378 | |
Language | eng | pt_BR |
Publisher | American Society for Microbiology | pt_BR |
Rights | open access | pt_BR |
Title | Nitro/nitrosyl ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death | pt_BR |
Type | Article | pt_BR |
DOI | 10.1128/AAC.02765-14 | |
Abstract | The cis–[RuCl(NO2)(dppb)(5,5’–mebipy)] (1), cis–[Ru(NO2)2(dppb)(5,5’–mebipy)] (2), ct–
[RuCl(NO)(dppb)(5,5’–mebipy)](PF6)2 (3) and cc–[RuCl(NO)(dppb)(5,5’–mebipy)]PF6 (4) complexes, where
5,5’–mebipy = 5,5’–dimethyl–2,2’-bipyridine and dppb = 1,4–bis(diphenylphosphino)butane, were synthesized
and characterized. The structure of the cis–[Ru(NO2)2(dppb)(5,5’–mebipy)] (2) complex was determined by X
ray crystallography. These complexes exhibited a higher anti-T. cruzi activity than benznidazole, the current
antiparasitic drug. Complex (3) was the most potent, displaying EC50 = 2.1±0.6 μM against trypomastigotes and
IC50 = 1.3±0.2 μM against amastigotes, while it displayed a CC50 of 51.4±0.2 μM in macrophages. It was
observed that the nitrosyl complex (3), but not its analog lacking the nitrosyl group, releases nitric oxide into
parasite cells. This release has a diminished effect on the trypanosomal protease cruzain, but induces substantial
parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and
finally results in cell death by necrosis. In infected mice, orally administered complex (3) (5 x 75 μmol/kg)
reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex
(3) indicated that its in vitro activity against trypomastigotes is synergic with benznidazole. In addition, drug
combination enhanced efficacy in infected mice, suggesting that ruthenium- nitrosyl complexes are potential
constituents for drug combinations. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | UFSCAR. Departamento de Química. São Carlos, SP, Brasil | pt_BR |
Affilliation | UFSCAR. Departamento de Química. São Carlos, SP, Brasil | pt_BR |
Affilliation | UFSCAR. Departamento de Química. São Carlos, SP, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / UNEB. Departamento de Ciências da Vida. Salvador, BA, Brasil | pt_BR |
Affilliation | USP. Instituto de Física de São Carlos. São Carlos, SP, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil | pt_BR |
Affilliation | UFSCAR. Departamento de Química. São Carlos, SP, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil | pt_BR |
Subject | Chagas disease | pt_BR |
Subject | Trypanosoma cruzi | pt_BR |
Subject | Ruthenium complexes | pt_BR |
Subject | Nitric oxide | pt_BR |
Subject | Autophagy | pt_BR |
Subject | Necrosis | pt_BR |