Abstract
Five heteroleptic compounds, [VVO(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 Trypanosoma cruzi as well as on VERO cells, as a mammalian cell model. Compounds showed activity against trypomastigotes with IC50 values of 0.29–3.02 μM. IN ligand and the new [VVO2(IN-H)] complex showed negligible activity. The most active compound [VVO(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. [VVO(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 × IC50 values of [VVO(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 C. elegans model showed no toxicity up to a 100 μM concentration of [VVO(IN-2H)(L2-H)]. This compound could be considered a prospective anti-T. cruzi agent that deserves further research.
Highlights
Chagas’ disease or American trypanosomiasis is a neglected tropical disease (NTDWHO), which is endemic in Latin America but has spread in recent decades to nonendemic regions owing to the migration of unaware infected people
The results show that the oxidovanadium(V) complex is an octahedral monomeric unit containing the doubly deprotonated IN ligand and monodeprotonated L2 in the coordination sphere
A new series of five structurally related mixed-ligand complexes, [VVO(IN-2H)(L-H)], where L are 8-hydroxyquinoline derivatives and IN is a tridentate Schiff base ligand derived from isoniazid, were synthesized and characterized in the solid state and in solution
Summary
Chagas’ disease or American trypanosomiasis is a neglected tropical disease (NTDWHO), which is endemic in Latin America but has spread in recent decades to nonendemic regions owing to the migration of unaware infected people. 8-hydroxyquinoline (8HQ) is considered a “privileged structure” in Medicinal Chemistry since it is a versatile chemical scaffold that deserves to be further exploited for therapeutic applications It can be modified and functionalized leading to derivatives, which may display favorable drug-like properties providing families of bioactive compounds [33,34,35]. Two homoleptic series [VIVO(L-H)2] and [VVO(OCH3)(L-H)2], with L = 8-hydroxyquinoline derivatives, were studied in depth to shed light into the significance of the presence of the tridentate co-ligand on the biological behavior of the vanadium compounds [42]. The biological activity of the whole series of oxidovanadium compounds and the ligands was evaluated against epimastigote and trypomastigote forms of T. cruzi as well as on VERO cells, as a mammalian cell model, for determining selectivity of the compounds towards the parasites. Five new heteroleptic oxidovanadium(V) complexes including the tridentate IN 8-hydroxyquinoline derivatives L0–L4 (Figure 1) were obtained with reasonable ligand yields
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