Novel ruthenium complexes as potential drugs for Chagas's disease: enzyme inhibition and <i>in vitro</i>/<i>in vivo</i> trypanocidal activity

Silva, Jean Jerley Nogueira; Guedes, Paulo Marcos da Matta; Zottis, Aderson; Balliano, Tatiane Luciano; Silva, Francisco Ordelei Nascimento; Lopes, Luiz Gonzaga de França; Ellena, Javier; Oliva, Glaucius; Andricopulo, Adriano D.; Franco, Douglas Wagner; Silva, João

doi:10.1111/j.1476-5381.2009.00524.x

Cited by 81 publications

(58 citation statements)

References 36 publications

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“…Actually, caviomorph rodents (i.e., guinea pigs and relatives) are particularly important because they have an ancient coevolutionary history with T. cruzi, widely spread in the American continent (138). The use of murine species has been fundamental for studies of T. cruzi infections aiming at the assessment of therapeutic regimes (89,364,410).…”

Section: Orders Of Mammals Infected By Trypanosoma Cruzimentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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SUMMARY Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8 + γδ, and CD8α + T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease.

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Section: Orders Of Mammals Infected By Trypanosoma Cruzimentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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“…Organic NO donor molecules have been investigated as anti-T. cruzi agents, but compounds with in vivo efficacy have not been identified (15). In recent years, ruthenium-nitrosyl complexes have been evaluated as anti-T. cruzi agents, demonstrating potent and selective antiparasitic activity, including in T. cruzi-infected mice (16)(17)(18)(19). In addition, this class of complexes exhibited inhibitory activity against the T. cruzi glyceraldehyde 3-phosphate dehydrogenase, suggesting that ruthenium-nitrosyl complexes may have pleiotropic effects (19).…”

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confidence: 99%

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

Bastos

Barbosa

Silva

et al. 2014

Antimicrob Agents Chemother

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e 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 M against trypomastigotes and a 50% inhibitory concentration (IC 50 ) of 1.3 ؎ 0.2 M against amastigotes, while it displayed a 50% cytotoxic concentration (CC 50 ) of 51.4 ؎ 0.2 M 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 mol/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.

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“…Moreover, three new flavonoids extracted from Neoraptua magnifica var. have showed inhibitory potentials [155]. Furthermore, several synthetic analogs of adenosine compounds had their inhibitory effect against GAPDH tested, showing promising results [156].…”

Section: Other Promising Targetsmentioning

confidence: 99%

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

Oliveira¹,

Mendes²,

Almeida³

et al. 2014

CRJ

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Abstract:Chagas disease is an infectious illness with a broad distribution throughout the South American and African continents, importantly influencing human morbidity and mortality and a controversial relationship with the onset of cancers, especially of the gastrointestinal tract system. In addition, it is listed by the World Health Organization (WHO) as one ofthe most neglected tropical diseases. Although Chagas disease (CD) was discovered more than 100 years ago, the existing therapies show low efficacy and serious side effects and developing safer and more effective drugs remains a hard challenge. Thus, this review highlights the main, novel and promising treatments against Trypanosoma cruzi, including biomacromolecules, natural products, vaccines, and metabolic pathway targets and highlights a worsening of esophageal cancer prognosis in chagasic patients. Moreover, we also discuss the perspectives of obtaining original optimized drugs that take advantage of organic and inorganic medicinal chemistry advances, as well as molecular modeling and biotechnology.

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Novel ruthenium complexes as potential drugs for Chagas's disease: enzyme inhibition and in vitro/in vivo trypanocidal activity

Cited by 81 publications

References 36 publications

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

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