Potential Mechanism of the Anti-trypanosomal Activity of Organoruthenium Complexes with Bioactive ThiosemicarbazonesReportar como inadecuado

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In the search for new metal-based drugs againstdiseases produced by trypanosomatid parasites, fourorganorutheniumII compounds Ru2p-cymene2L2X2, where L are bioactive 5-nitrofuryl-containingthiosemicarbazones and X=Cl or PF6, had been previouslyobtained. These compounds had shown activity onTrypanosoma brucei, the etiological agent of Africantrypanosomiasis. Because of genomic similarities betweentrypanosomatides, these ruthenium compoundswere evaluated, in the current work, on Trypanosomacruzi, the parasite responsible of American trypanosomiasisChagas disease. Two of them showed significantin vitro growth inhibition activity against theinfective trypomastigote form of T. cruzi Dm28c clone,IC50=11.69 and 59.42 μM for Ru2p-cymene2L42Cl2and Ru2p-cymene2L12Cl2, respectively, where HL4=5-nitrofuryl-N-phenylthiosemicarbazone and HL1=5-nitrofurylthiosemicarbazone, showing fairly good selectivitiestoward trypanosomes with respect to mammaliancells J774 murine macrophages. Moreover, Ru2p-cymene2L22Cl2, where HL2=5-nitrofuryl-Nmethylthiosemicarbazone,was synthesized in order to evaluatethe effect of improved solubility on biological behavior.This new chloride salt showed higher activity against T. cruzithan that of the previously synthesized hexafluorophosphateone Dm28c clone, IC50=14.30 μM for the former and231.3 μM for the latter. In addition, the mode ofantitrypanosomal action of the organoruthenium compounds was investigated. The complexes were not only able togenerate toxic free radicals through bioreduction but they alsointeracted with two further potential parasite targets: DNA andcruzipain, a cysteine protease which plays a fundamental rolein the biological cycle of these parasites. The results suggest a-multi-target- mechanism of trypanosomicidal action for theobtained complexes.Nota general

Artículo de publicación ISI

Autor: Demoro, Bruno; - Rossi, Miriam; - Caruso, Francesco; - Liebowitz, Daniel; - Olea Azar, Claudio; - Kemmerling Weis, Ulrique; - May

Fuente: http://repositorio.uchile.cl/


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