AUTHOR=Scalese Gonzalo , Machado Ignacio , Salazar Fabiana , Coitiño E. Laura , Correia Isabel , Pessoa João Costa , Pérez-Díaz Leticia , Gambino Dinorah 

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

JOURNAL=Frontiers in Chemical Biology

VOLUME=2

YEAR=2024

URL=https://www.frontiersin.org/journals/chemical-biology/articles/10.3389/fchbi.2023.1304571

DOI=10.3389/fchbi.2023.1304571

ISSN=2813-530X

ABSTRACT=<p>Searching for new prospective drugs against Chagas disease (American trypanosomiasis) and Leishmaniasis, a series of five heteroleptic vanadium compounds, [V<sup>IV</sup>O(L-H)(mpo)], where L are 8-hydroxyquinoline derivatives and mpo is 2-mercaptopyridine <italic>N</italic>-oxide, are synthesized and characterized. Comprehensive characterizations are conducted in solid state and in solution. The compounds are evaluated on epimastigotes and trypomastigotes of <italic>Trypanosoma cruzi</italic> and in promastigotes of <italic>Leishmania infantum</italic>, alongside on VERO cells, as a mammalian cell model. The compounds exhibit activity against both forms of <italic>T. cruzi</italic> and promastigotes of <italic>L. infantum</italic>, with the trypomastigote infective stage of <italic>T. cruzi</italic> displaying the highest sensitivity. The most selective vanadium compound [V<sup>IV</sup>O(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. [V<sup>IV</sup>O(L2-H)(mpo)] significantly impacted the infection potential of cell-derived trypomastigotes and hindered the replication of the <italic>T. cruzi</italic> amastigote form. Low total vanadium uptake by <italic>T. cruzi</italic> 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 V<sup>IV</sup>O 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, [V<sup>IV</sup>O(L-H)(mpo)] complexes could be considered interesting anti-<italic>T. cruzi</italic> agents that deserve further research.</p>