Vanadium has demonstrated a variety of roles in biological systems, and its therapeutic applications have been proposed for various diseases, mainly diabetes and cancer. Most of vanadium medicinal chemistry is based on the VIVO2+, VVO2+, and VVO3+ moieties, with the oxidovanadium(IV) and (V) species acting as pivotal players [[1], [2], [3], [4], [5], [6], [7]]. Furthermore, many oligomeric vanadium compounds have gained relevance, expanding the scope of vanadium's medicinal properties [8].

Over the last two decades, our group has pioneered the development of vanadium compounds as drug candidates for highly prevalent parasitic illnesses [7,[9], [10], [11], [12], [13], [14], [15], [16]]. Among them, Chagas disease (also called American Trypanosomiasis) and Leishmaniasis predominantly impact low-income populations in developing regions of the world and coexist in South America. Both diseases are caused by related trypanosomatid parasites Trypanosoma cruzi (T. cruzi) and Leishmania spp, respectively. Chagas disease affects more than 6 million people and is primarily spread to humans through the bite of infected Triatominae insects. Nowadays, the infection has spread to non-endemic regions through organ transplantation, blood transfusions and congenital transmissions due to the migration of people in the silent indeterminate phase of the disease [[17], [18], [19], [20], [21]]. Leishmaniasis is mainly transmitted to mammals by the bite of female infected sandflies, and impacts around 350 million people across nearly a hundred countries on four continents. Three forms with varying severity are known: mucocutaneous, cutaneous and visceral leishmaniasis, the last of which can be fatal if left untreated [19,[22], [23], [24], [25], [26]].

Due to the pharmaceutical industry's lack of interest in drug development, both diseases were classified by the World Health Organization (WHO) as Neglected Tropical Diseases (NTD) [[17], [18], [19], [20]]. Current chemotherapy causes significant adverse effects mainly due to their toxicity and varying levels of susceptibility and drug resistance against various strains of the parasites [19,20,23,25].

In the quest for new treatments, Inorganic Medicinal Chemistry has proven to be a fertile ground for the development of novel metal-based drug candidates for combating parasitic diseases [7,9,[27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42]]. Our key strategy in this field involves developing metal coordination compounds, a powerful tool for assembling new molecules that integrate bioactive ligands into a single compound. By coordinating the bioactive ligands to metal centers, it is possible to enhance their physicochemical properties, such as lipophilicity, stability, electronic structure, and transport characteristics, often leading to compounds with improved biological activity and/or reduced toxicity compared to the free ligands.

The 8-hydroxyquinoline (8HQ) scaffold has been highlighted as an important structure in medicinal chemistry due to the variety of biological properties observed for both organic and inorganic derivatives [[43], [44], [45], [46]]. In recent years, we developed several series of both homoleptic and heteroleptic vanadium (IV) and (V) coordination compounds that incorporate this general scaffold and their substituted derivatives in the vanadium coordination sphere. Most of V-8HQ derivative complexes previously developed by us showed promising biological activity against clinically relevant forms of trypanosomatid parasites [13,14,16,47].

Series of heteroleptic oxidovanadium(V) compounds featuring double deprotonated tridentate salicylaldehyde semicarbazones as coligands have highlighted the crucial role of the presence and nature of the tridentate coligand in modulating the biological behavior of the resulting compounds [13]. Accordingly, we have expanded the series by substituting the salicylaldehyde semicarbazone by a hydrazone derived from 2-hydroxynaphthaldehyde and isoniazid [14,48]. The resulting oxidovanadium(V) series [VVO(IN-2H)(L-H)] (Fig. 1A), where IN is the tridentate Schiff base ligand 2-hydroxy-1-naphtaldehyde isonicotinoyl hydrazone and L are 8-hydroxyquinoline derivatives (Fig. 1B), showed interesting activity against the extracellular forms of T. cruzi (non-infective replicative epimastigotes and infective non-replicative trypomastigotes). The latter demonstrated greater sensitivity to these VVO-compounds, which exhibit up to seventy times higher potency than the reference drug Nifurtimox, with low in vivo toxicity confirmed [14]. Aiming to further modulate the physicochemical properties of the VVO-8HQ compounds, in this work a new series of heteroleptic compounds was developed including the structurally related Schiff base 5-bromo salicylaldehyde isonicotinoyl hydrazone (BrIS, Fig. 1C), that has demonstrated less cytotoxicity compared to IN on macrophages derived from the human monocytes THP-1 (unpublished results, preliminary data in Table S1), which are widely used in biomedical research due to its characteristics that enable modeling immune responses and studying cellular functions related to monocytes and macrophages.

The new series includes five oxidovanadium(V) compounds, [VVO(BrIS-2H)(L-H), where L represents L0-L4 (Fig. 1D). They were synthesized and characterized in both solid state and in solution. The compounds were evaluated on T. cruzi epimastigotes and trypomastigotes as well as on promastigotes of L. infantum. Additionally, the toxicity was assessed on VERO cells as mammalian model. The most promising compound in the series was further tested against T. cruzi infections. Moreover, the percentage of vanadium uptaken and its preferential association with selected biomolecules in T. cruzi were analyzed. The generation of ROS species and the effect on the integrity of mitochondrial membrane potential in the parasite were also studied aiming to link the biochemical changes induced by the VVO- compounds to their antiparasitic activity. With the aim of refining our strategy, the entire set of emerging results was compared to data from previous work on oxidovanadium(V) complexes featuring bidentate bioactive ligands.