New heteroleptic oxidovanadium(V) complexes: synthesis, characterization and biological evaluation as potential agents against Trypanosoma cruzi

Abstract

Searching for prospective vanadium-based agents against Trypanosoma cruzi, the parasite causing Chagas disease, four new [VO(8HQ-H)(L-2H)] compounds, where 8HQ is 8-hydroxyquinoline and L are tridentate salicylaldehyde semicarbazone derivatives L1-L4, were synthesized and characterized in the solid state and in solution. The compounds were evaluated on T. cruzi epimastigotes (CL Brener) as well as on VERO cells, as mammalian cell model. Compounds showed activity against T. cruzi (IC 6.2-10.5 μM) of the same order than Nifurtimox and 8HQ, and a four- to sevenfold activity increase with respect to the free semicarbazones. For comparison, [VO(L-H)] series was prepared and the new [VO(L3-H)] was fully characterized. They showed negligible activity and low selectivity towards the parasite. The inclusion of 8HQ as ligand in [VO(8HQ-H)(L-2H)] compounds led to good activities and increased selectivity towards the parasite with respect to 8HQ. V NMR experiments, performed to get insight into the nature of the active species, suggested partial decomposition of the compounds in solution to [VO(L-H)] and 8HQ. Depending on the dose, the compounds act as trypanocide or trypanostatic. A high uptake of vanadium in the parasites (58.51-88.9% depending on dose) and a preferential accumulation in the soluble protein fraction of the parasite was determined. Treated parasites do not seem to show a late apoptotic/necrotic phenotype suggesting a different cell death mechanism. In vivo toxicity study on zebrafish model showed no toxicity up to a 25 µM concentration of [VO(8HQ-H)(L1-2H)]. These compounds could be considered prospective anti-T. cruzi agents that deserve further research.

Heteroleptic Oxidovanadium(V) Complexes with Activity against Infective and Non-Infective Stages of Trypanosoma cruzi

“…The FTIR pattern of the new [V V O 2 (IN-H)] compound was similar to that previously reported for similar dioxidovanadium(V) complexes with semicarbazone ligands ( Figure S7 ) [ 41 , 46 , 49 , 51 , 52 ]. The shift of ν(C=O) and ν(C=N) bands and the non-observation of the ν(OH) are in agreement with tridentate coordination through the carbonylic oxygen, the azomethyne nitrogen and the phenolic oxygen, and with deprotonation of the semicarbazone ligand at the phenolic hydroxyl group.…”

“…All [V V O(IN-2H)(L-H)] complexes showed a similar spectroscopic behavior. Based on our previous reports on vibrational behavior of heteroleptic oxidovanadium(V) complexes and homoleptic oxidovanadium(IV) and (V) complexes with 8-hydroxyquinoline derivatives and reports for other related complexes, selected IR bands of the new [V V O(IN-2H)(L-H)] complexes were identified and tentatively assigned ( Supplementary Materials Table S1 ) [ 31 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

“…Instead, bands at ca. 1620 cm −1 and 1593 cm −1 are observed which are characteristic of a single CO bond typical of the coordination of the ligand enolate form ( Figure S1 ) [ 31 , 32 , 41 , 46 , 50 ]. The simultaneous presence of the semicarbazone ligand L and the 8-hydroxyquinoline derivative co-ligand in the coordination sphere of vanadium led to quite complex spectra, particularly in the 1600–1500 cm −1 region ( Figures S2–S6 ), where bands due to ν(C=C) and ν(C=N) of heterocyclic compounds usually appear.…”

“…In particular, 8HQ and some of its derivatives have shown antiparasitic activity and 8HQ metal complexes have demonstrated different biological activities [ 36 , 37 , 38 , 39 , 40 ]. Four bioactive oxidovanadium(V) heteroleptic compounds including 8HQ were developed and their biological behavior on T. cruzi was studied in detail [ 41 ]. More recently, two homoleptic series [V IV O(L-H) 2 ] and [V V O(OCH 3 )(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 ].…”

New Antimicrobial Strategies Based on Metal Complexes

“…Several publications dealing with vanadium complexes for potential antitrypanosomal treatment are available, and some of this work was done by the group of Dinorah Gambino. They proposed several vanadium complexes based on salicylaldehyde-and polypyridyl-derivatives ligands [141][142][143]. Another example is a vanadium complex of aminophen and bromosalycilaldehyde (Figure 18, compound 24), whose IC 50 was shown to be in the low micromolar range (0.27-3.8 µM) [144,145] against T. cruzi, similar to the standard drug nifurtimox, but a live/dead assay only resulted in a trypanostatic effect, with the parasites recovering to normal growth after the cutting off treatment.…”