Nitro/nitrosyl-ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death.
Antimicrob Agents Chemother
; 58(10): 6044-55, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-25092707
ABSTRACT
cis-[RuCl(NO2)(dppb)(5,5'-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5'-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 4), where 5,5'-mebipy is 5,5'-dimethyl-2,2'-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 µM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 µM against amastigotes, while it displayed a 50% cytotoxic concentration (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 (five times at a dose of 75 µmol/kg of body weight) 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Compostos Organometálicos
/
Rutênio
/
Autofagia
/
Tripanossomicidas
/
Trypanosoma cruzi
/
Compostos Nitrosos
Limite:
Animals
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Brasil