Facing diseases caused by trypanosomatid parasites: rational design of multifunctional oxidovanadium(IV) complexes with bioactive ligands

Abstract

Searching for new prospective drugs against Chagas disease (American trypanosomiasis) and Leishmaniasis, a series of five heteroleptic vanadium compounds, [VIVO(L-H)(mpo)], where L are 8-hydroxyquinoline derivatives and mpo is 2-mercaptopyridine N-oxide, are synthesized and characterized. Comprehensive characterizations are conducted in solid state and in solution. The compounds are evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi and in promastigotes of Leishmania infantum, alongside on VERO cells, as a mammalian cell model. The compounds exhibit activity against both forms of T. cruzi and promastigotes of L. infantum, with the trypomastigote infective stage of T. cruzi displaying the highest sensitivity. The most selective vanadium compound [VIVO(L2-H)(mpo)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, globally shows adequate selectivity towards the parasite and was selected to carry out further in-depth biological studies. [VIVO(L2-H)(mpo)] significantly impacted the infection potential of cell-derived trypomastigotes and hindered the replication of the T. cruzi amastigote form. Low total vanadium uptake by T. cruzi parasites and preferential accumulation in the soluble proteins fraction, with negligible localization in the DNA fraction, are determined. A trypanocide effect is observed across various concentrations of the compound. The generation of oxidative stress and the induction of mitochondria-dependent apoptosis are proposed as the main mechanisms of the parasite’s death by the VIVO compounds. Both theoretical predictions and experimental data support the hypothesis that inhibiting the parasite-specific enzyme NADH-fumarate reductase activity plays a crucial role in the trypanocidal action of these complexes. Globally, [VIVO(L-H)(mpo)] complexes could be considered interesting anti-T. cruzi agents that deserve further research.

Metallomics: An Essential Tool for the Study of Potential Antiparasitic Metallodrugs

“…This differential uptake could partially explain the much higher activity on the parasite of the Pt compound in respect to the Pd analogue. A similar behavior was observed for [V IV O­(L2-H)­(mpo)] with L2 = 5-chloro-7-iodo-8-hydroxyquinoline and mpo = pyridine-2-thiolate-1-oxide …”

“…For [V V O­(IN-2H)­(L2-H)] the vanadium uptake on the infective trypomastigote form of the parasite was higher than on the epimastigote life cycle form present in the infected bug responsible for the parasite transmission. This correlates well with a higher activity of the compound on the biologically relevant trypomastigote form circulating in the mammalian host blood …”

“…In this context, Gambino’s group has been working during the last 20–25 years on the rational design of novel metal-based compounds bearing activity against these trypanosomatid parasites, with a particular focus on the causative agent of Chagas disease, Trypanosoma cruzi. − , Although metallomics and omics studies in general have been performed in the development of anticancer metal-based drugs, an omics strategy had not been explored for unraveling the mechanism of action of antiparasitic metal-based prospective drugs. Knowing the significance of omics studies in drug development, metallomics, proteomics, and transcriptomics of several metal-based compounds were performed for the first time in Trypanosoma cruzi by us. − The current review involves the comparative study of the new knowledge obtained by our group through this approach.…”

“…In this regard, we have focused our attention on the rational design of antiparasitic metal compounds based on the relationships between chemical structure, physicochemical properties, and biological activity obtained in our investigations. This research line has led to important contributions that have been transferred to the scientific field, showing the vital importance of cellular uptake metallomic studies to understand the fate of potential metallodrugs and elucidate targets and mechanisms of action. − Table summarizes the uptake results obtained after metallomics studies of different metal-based compounds performed on epimastigotes of Trypanosoma cruzi. The molecular structures of the bioactive compounds are shown in Figure .…”

“…A similar behavior was observed for [V IV O(L2-H)(mpo)] with L2 = 5-chloro-7-iodo-8-hydroxyquinoline and mpo = pyridine-2-thiolate-1-oxide. 45 …”