| Summary: | Five heteroleptic compounds, [V<sup>V</sup>O(IN-2H)(L-H)], where L are 8-hydroxyquinoline derivatives and IN is a Schiff base ligand, were synthesized and characterized in both the solid and solution state. The compounds were evaluated on epimastigotes and trypomastigotes of <i>Trypanosoma cruzi</i> as well as on VERO cells, as a mammalian cell model. Compounds showed activity against trypomastigotes with IC<sub>50</sub> values of 0.29–3.02 μM. IN ligand and the new [V<sup>V</sup>O<sub>2</sub>(IN-H)] complex showed negligible activity. The most active compound [V<sup>V</sup>O(IN-2H)(L2-H)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, showed good selectivity towards the parasite and was selected to carry out further biological studies. Stability studies suggested a partial decomposition in solution. [V<sup>V</sup>O(IN-2H)(L2-H)] affects the infection potential of cell-derived trypomastigotes. Low total vanadium uptake by parasites and preferential accumulation in the soluble proteins fraction were determined. A trypanocide effect was observed when incubating epimastigotes with 10 × IC<sub>50</sub> values of [V<sup>V</sup>O(IN-2H)(L2-H)] and the generation of ROS after treatments was suggested. Fluorescence competition measurements with DNA:ethidium bromide adduct showed a moderate DNA interaction of the complexes. In vivo toxicity study on <i>C. elegans</i> model showed no toxicity up to a 100 μM concentration of [V<sup>V</sup>O(IN-2H)(L2-H)]. This compound could be considered a prospective anti-<i>T. cruzi</i> agent that deserves further research.
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