Clioquinol

Chagas disease and Leishmaniasis, caused by Trypanosoma cruzi and Leishmania spp., respectively, are highly prevalent neglected tropical diseases (NTDs) that pose significant global health challenges. In our pursuit of effective vanadium-based therapeutics against these diseases, we previously developed several series of oxidovanadium(V) complexes featuring bidentate bioactive ligands and Schiff base tridentate ligands. The current study extends our previous research by incorporating in the same molecule, a tridentate bromo-substituted isonicotinyl hydrazone Schiff base ligand, BrIS, and a 8-hydroxyquinoline derivative (L), leading to the synthesis and comprehensive characterization of five new complexes, [V^VO(BrIS-2H)(L-H)]. Most of new complexes exhibited activity in the micromolar range against the infective trypomastigote form of T. cruzi (EC_{50, 24h}: 0.73-7.95 μM) and against L. infantum promastigotes (IC_{50, 5 days}: 1.14-1.16 μM) and some of them showed good selectivity indexes towards the parasites (SI up to 52). Notably, the vanadium uptake by the parasites was higher for the new [V^VO(BrIS-2H)(L-H)] compounds compared to [V^VO(IN-2H)(L-H)] analogues previously developed, where IN is the structurally related 2-hydroxy-1-naphtaldehyde isonicotinoylhydrazone ligand, with accumulation in the soluble cell fraction. High-dose incubations resulted in trypanocidal effects and suggested the generation of reactive oxygen species (ROS). Further analysis revealed that [V^VO(BrIS-2H)(L-H)] complexes induced a higher percentage of apoptosis, whereas the [V^VO(IN-2H)(L-H)] series was associated with autophagic cell death. These findings highlight the potential of the [V^VO(BrIS-2H)(L-H)] series as promising anti-T. cruzi agents and underscore the need for further research to optimize their therapeutic efficacy and explore their mechanisms of action.

Tuberculosis (TB) remains a major worldwide healthcare issue, with anti-TB drugs playing a pivotal role in its treatment. However, the emergence of anti-TB drug-induced liver injury (ATB-DILI) poses a considerable challenge, undermining treatment efficacy and patient survival. This study investigates the underlying mechanisms of ATB-DILI, focusing on reactive oxygen species (ROS), mitophagy, lysosomal function, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. A rat hepatocyte model treated with standard anti-TB drugs was established to assess liver inflammation, oxidative stress biomarkers, mitochondrial function, and mitophagy processes. The results indicate that anti-TB drug administration induced significant inflammatory injury, characterized by elevated IL-6 and reduced IL-4 and IL-10 levels. ROS overproduction predominantly originates in the mitochondrial level, consequently resulting in oxidative stress and impaired mitochondrial function. A noticeable decline in both the oxygen consumption rate and ATP production is indicative of this phenomenon. Although mitophagy was activated, impaired lysosomal function hindered mitophagic flux, leading to the buildup of damaged mitochondria and ROS. Pharmacological intervention with mitoTEMPO alleviated mitochondrial dysfunction, while clioquinol restored lysosomal function and improved mitophagy. Additionally, the cGAS-STING signaling pathway was found to regulate inflammation in ATB-DILI, with both mitoTEMPO and clioquinol alleviating its effects. These findings elucidate the crucial impact of lysosome-mediated mitophagy dysfunction and mitochondrial ROS in ATB-DILI, highlighting potential therapeutic targets to enhance liver protection during anti-TB treatment.