Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/8378
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dc.contributor.authorBastos, Tanira Matutino
dc.contributor.authorBarbosa, Marília Imaculada Frazão
dc.contributor.authorSilva, Monize Martins da
dc.contributor.authorJosé Júnior, W. da C
dc.contributor.authorMeira, Cássio Santana
dc.contributor.authorGuimarães, Elisalva Teixeira
dc.contributor.authorEllena, Javier Alcides
dc.contributor.authorMoreira, Diogo Rodrigo Magalhães
dc.contributor.authorBatista, Alzir Azevedo
dc.contributor.authorSoares, Milena Botelho Pereira
dc.date.accessioned2014-09-15T17:29:28Z
dc.date.available2014-09-15T17:29:28Z
dc.date.issued2014
dc.identifier.citationBASTOS, 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.
dc.identifier.issn0066-4804
dc.identifier.urihttps://www.arca.fiocruz.br/handle/icict/8378
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.rightsopen access
dc.titleNitro/nitrosyl ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death
dc.typeArticle
dc.identifier.doi10.1128/AAC.02765-14
dc.description.abstractenThe 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.
dc.creator.affilliationFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
dc.creator.affilliationUFSCAR. Departamento de Química. São Carlos, SP, Brasil
dc.creator.affilliationUFSCAR. Departamento de Química. São Carlos, SP, Brasil
dc.creator.affilliationUFSCAR. Departamento de Química. São Carlos, SP, Brasil
dc.creator.affilliationFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
dc.creator.affilliationFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / UNEB. Departamento de Ciências da Vida. Salvador, BA, Brasil
dc.creator.affilliationUSP. Instituto de Física de São Carlos. São Carlos, SP, Brasil
dc.creator.affilliationFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil
dc.creator.affilliationUFSCAR. Departamento de Química. São Carlos, SP, Brasil
dc.creator.affilliationFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil
dc.subject.enChagas disease
dc.subject.enTrypanosoma cruzi
dc.subject.enRuthenium complexes
dc.subject.enNitric oxide
dc.subject.enAutophagy
dc.subject.enNecrosis
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