Repurposing Analysis of Nitroxoline (8-Hydroxy-5-nitroquinoline) as an Antichagasic Compound.

Chagas disease, caused by the protozoan parasite , remains a major neglected tropical disease, with over six million cases concentrated, primarily in Latin America. Despite decades of research, treatment continues to rely on two outdated drugs-benznidazole and nifurtimox-both of which exhibit limited efficacy and are associated with severe side effects. In this context, drug repurposing presents a promising strategy to accelerate the development of safer and more effective therapies. Nitroxoline, a hydroxyquinoline compound widely used in Europe to treat bacterial urinary tract infections, has recently garnered attention for its broad-spectrum antimicrobial and anticancer activities. This study evaluated the antitrypanosomal potential of nitroxoline against both epimastigote and intracellular amastigote forms of , demonstrating significantly greater efficacy than benznidazole. In addition to its antiparasitic activity, we investigated the mechanism of parasite death and found that nitroxoline induces hallmarks of programmed cell death, including chromatin condensation, mitochondrial membrane depolarization, ATP depletion, reactive oxygen species accumulation, and increased membrane permeability. These cellular events are critical for minimizing host tissue inflammation and suggest a safer therapeutic profile. The nitroxoline was shown to induce greater activity than the reference treatment, benznidazole, in addition to triggering events related to apoptotic or silent cell death. Given its established clinical use and favorable safety data, nitroxoline emerges as a strong candidate for further investigation as a repurposed treatment for Chagas disease. Future work should focus on in vivo efficacy, pharmacokinetics, and drug delivery strategies to enhance systemic bioavailability.