title: Nitro/nitrosyl-ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death.
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.
authors.affiliation: FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, Salvador, Bahia, Brazil.
authors.forename: Tanira M
authors.initials: TM
authors.lastname: Bastos
authors.affiliation: UFSCAR, Departamento de Química, São Carlos, São Paulo, Brazil.
authors.forename: Marília I F
authors.initials: MI
authors.lastname: Barbosa
authors.affiliation: UFSCAR, Departamento de Química, São Carlos, São Paulo, Brazil.
authors.forename: Monize M
authors.initials: MM
authors.lastname: da Silva
authors.affiliation: UFSCAR, Departamento de Química, São Carlos, São Paulo, Brazil.
authors.forename: José W
authors.initials: JW
authors.lastname: da C Júnior
authors.affiliation: FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, Salvador, Bahia, Brazil.
authors.forename: Cássio S
authors.initials: CS
authors.lastname: Meira
authors.affiliation: FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, Salvador, Bahia, Brazil UNEB, Departamento de Ciências da Vida, Salvador, Bahia, Brazil.
authors.forename: Elisalva T
authors.initials: ET
authors.lastname: Guimaraes
authors.affiliation: USP, Instituto de Física de São Carlos, São Carlos, São Paulo, Brazil.
authors.forename: Javier
authors.initials: J
authors.lastname: Ellena
authors.affiliation: FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, Salvador, Bahia, Brazil Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, Bahia, Brazil.
authors.forename: Diogo R M
authors.initials: DR
authors.lastname: Moreira
authors.affiliation: UFSCAR, Departamento de Química, São Carlos, São Paulo, Brazil.
authors.forename: Alzir A
authors.initials: AA
authors.lastname: Batista
authors.affiliation: FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, Salvador, Bahia, Brazil Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, Bahia, Brazil milenabpsoares@gmail.com.
authors.forename: Milena B P
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009603:Nitroso Compounds / Q000737:chemistry / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D009603:Nitroso Compounds; D009942:Organometallic Compounds; D014344:Trypanocidal Agents; D012428:Ruthenium
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