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.

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites

“…This mechanism of action seems to be retained by other previously reported metal complexes of these bioactive ligands [21][22][23]27,29,31,33]. As previously stated, the first step of this mechanism involves the one electron reduction of the nitro moiety.…”

“…Among the selected bioactive ligands a family of thiosemicarbazones containing the 5-nitrofuryl pharmacophore has been extensively studied by us [13]. We have rationally designed and developed more than sixty compounds of these ligands including palladium, platinum and ruthenium classical complexes as well as ruthenium η 6 -arene organometallic compounds and the effect of metal complexation and the presence of different co-ligands on the pharmacological profile of these bioactive ligands was evaluated [21][22][23][24][25][26][27][28][29][30][31][32][33].…”

Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs

“…Therefore both the affinity of gold(III) complexes for thiol and selenol containing proteins can be used to target parasite enzymes such as cysteine proteases as the production of reactive oxygen species in intracellular level could cause injury to the parasites [13,15]. Despite of the high potential of gold(III) complexes in this area, only a few examples have been evaluated against parasitic diseases [13,14,17].…”

A new ruthenium cyclopentadienyl azole compound with activity on tumor cell lines and trypanosomatid parasites

“…In this perspective, ruthenium-cyclopentadienyl complexes presenting N-heteroaromatic ligands have exhibited excellent antitumoral properties and are very promising agents for cancer therapy [30][31][32][33][34]. In addition, ruthenium classical coordination compounds and organometallic compounds have been recognized as prospective agents against trypanosomatid parasites [35][36][37][38][39][40][41][42]. The design of antiparasitic compounds which combine ligands bearing antitrypanosomal activity and pharmacologically active metals in a single chemical entity could provide drugs capable of modulating multiple targets simultaneously.…”

“…The design of antiparasitic compounds which combine ligands bearing antitrypanosomal activity and pharmacologically active metals in a single chemical entity could provide drugs capable of modulating multiple targets simultaneously. Our group has been working on the development of ruthenium complexes with different families of trypanosomicidal ligands [10,21,[38][39][40][41][42]. In particular, Ru-p-cymene compounds with this type of ligands were developed and studied in depth [39][40][41].…”