In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 10 ( 2014-10), p. 6044-6055
Abstract:
cis -[RuCl(NO 2 )(dppb)(5,5′-mebipy)] (complex 1), cis -[Ru(NO 2 ) 2 (dppb)(5,5′-mebipy)] (complex 2), ct -[RuCl(NO)(dppb)(5,5′-mebipy)](PF 6 ) 2 (complex 3), and cc -[RuCl(NO)(dppb)(5,5′-mebipy)](PF 6 ) 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 (EC 50 ) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC 50 ) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC 50 ) 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.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.02765-14
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2014
detail.hit.zdb_id:
1496156-8
SSG:
12
SSG:
15,3
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