title: Potential mechanism of the anti-trypanosomal activity of organoruthenium complexes with bioactive thiosemicarbazones.
abstract: In the search for new metal-based drugs against diseases produced by trypanosomatid parasites, four organoruthenium(II) compounds [Ru2(p-cymene)2(L)2]X2, where L are bioactive 5-nitrofuryl-containing thiosemicarbazones and X = Cl or PF6, had been previously obtained. These compounds had shown activity on Trypanosoma brucei, the etiological agent of African trypanosomiasis. Because of genomic similarities between trypanosomatides, these ruthenium compounds were evaluated, in the current work, on Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas disease). Two of them showed significant in vitro growth inhibition activity against the infective trypomastigote form of T. cruzi (Dm28c clone, IC50 = 11.69 and 59.42 μM for [Ru2(p-cymene)2(L4)2]Cl2 and [Ru2(p-cymene)2(L1)2]Cl2, respectively, where HL4 = 5-nitrofuryl-N-phenylthiosemicarbazone and HL1 = 5-nitrofurylthiosemicarbazone), showing fairly good selectivities toward trypanosomes with respect to mammalian cells (J774 murine macrophages). Moreover, [Ru2(p-cymene)2(L2)2]Cl2, where HL2 = 5-nitrofuryl-N-methylthiosemicarbazone, was synthesized in order to evaluate the effect of improved solubility on biological behavior. This new chloride salt showed higher activity against T. cruzi than that of the previously synthesized hexafluorophosphate one (Dm28c clone, IC50 = 14.30 μM for the former and 231.3 μM for the latter). In addition, the mode of antitrypanosomal action of the organoruthenium compounds was investigated. The complexes were not only able to generate toxic free radicals through bioreduction but they also interacted with two further potential parasite targets: DNA and cruzipain, a cysteine protease which plays a fundamental role in the biological cycle of these parasites. The results suggest a "multi-target" mechanism of trypanosomicidal action for the obtained complexes.
authors.affiliation: Cátedra de Química Inorgánica, Departamento Estrella Campos, Facultad de Química, Universidad de la República (UdelaR), Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Bruno
authors.initials: B
authors.lastname: Demoro
authors.forename: Miriam
authors.initials: M
authors.lastname: Rossi
authors.forename: Francesco
authors.initials: F
authors.lastname: Caruso
authors.forename: Daniel
authors.initials: D
authors.lastname: Liebowitz
authors.forename: Claudio
authors.initials: C
authors.lastname: Olea-Azar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kemmerling
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
authors.forename: Helena
authors.initials: H
authors.lastname: Guiset
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Chiara
authors.initials: C
authors.lastname: Pizzo
authors.forename: Graciela
authors.initials: G
authors.lastname: Mahler
authors.forename: Lucía
authors.initials: L
authors.lastname: Otero
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D018625:Microscopy, Atomic Force; D009930:Organic Chemicals / Q000737:chemistry / Q000494:pharmacology*; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009930:Organic Chemicals; D017975:Ruthenium Compounds; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents