Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/8378
Title: Nitro/nitrosyl ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death
Authors: Bastos, Tanira Matutino
Barbosa, Marília Imaculada Frazão
Silva, Monize Martins da
José Júnior, W. da C
Meira, Cássio Santana
Guimarães, Elisalva Teixeira
Ellena, Javier Alcides
Moreira, Diogo Rodrigo Magalhães
Batista, Alzir Azevedo
Soares, Milena Botelho Pereira
Affilliation: Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
UFSCAR. Departamento de Química. São Carlos, SP, Brasil
UFSCAR. Departamento de Química. São Carlos, SP, Brasil
UFSCAR. Departamento de Química. São Carlos, SP, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / UNEB. Departamento de Ciências da Vida. Salvador, BA, Brasil
USP. Instituto de Física de São Carlos. São Carlos, SP, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil
UFSCAR. Departamento de Química. São Carlos, SP, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil
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.
Keywords: Chagas disease
Trypanosoma cruzi
Ruthenium complexes
Nitric oxide
Autophagy
Necrosis
Issue Date: 2014
Publisher: American Society for Microbiology
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.
DOI: 10.1128/AAC.02765-14
ISSN: 0066-4804
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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