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Despite decades of research, treatment continues to rely on two outdated drugs\u2014benznidazole and nifurtimox\u2014both of which exhibit limited efficacy and are associated with severe side effects.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 T. cruzi, demonstrating significantly greater efficacy than benznidazole. Methods: 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. Results: 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. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/ph18081106","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:38:41Z","timestamp":1753443521000},"page":"1106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Repurposing Analysis of Nitroxoline (8-Hydroxy-5-nitroquinoline) as an Antichagasic Compound"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3486-7740","authenticated-orcid":false,"given":"Carlos J.","family":"Bethencourt-Estrella","sequence":"first","affiliation":[{"name":"Instituto Universitario de Enfermedades Tropicales y Salud P\u00fablica de Canarias, Universidad de La Laguna, Avda. Astrof\u00edsico Fco. S\u00e1nchez, S\/N, 38203 La Laguna, Spain"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Pediatr\u00eda, Medicina Preventiva y Salud P\u00fablica, Toxicolog\u00eda, Medicina Legal y Forense y Parasitolog\u00eda, Universidad de La Laguna, 38203 La Laguna, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0675-8221","authenticated-orcid":false,"given":"Atteneri","family":"L\u00f3pez-Arencibia","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Enfermedades Tropicales y Salud P\u00fablica de Canarias, Universidad de La Laguna, Avda. Astrof\u00edsico Fco. S\u00e1nchez, S\/N, 38203 La Laguna, Spain"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Pediatr\u00eda, Medicina Preventiva y Salud P\u00fablica, Toxicolog\u00eda, Medicina Legal y Forense y Parasitolog\u00eda, Universidad de La Laguna, 38203 La Laguna, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel M.","family":"Calero-Docina","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Enfermedades Tropicales y Salud P\u00fablica de Canarias, Universidad de La Laguna, Avda. Astrof\u00edsico Fco. S\u00e1nchez, S\/N, 38203 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7075-5378","authenticated-orcid":false,"given":"Frieder","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Medical Faculty, University of Cologne, 50933 Cologne, Germany"},{"name":"Department of Microbiology and Hospital Hygiene, Bundeswehr Central Hospital Koblenz, 56072 Koblenz, Germany"},{"name":"Landesuntersuchungsamt Rheinland-Pfalz, 56068 Koblenz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Scheid","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Hospital Hygiene, Bundeswehr Central Hospital Koblenz, 56072 Koblenz, Germany"},{"name":"Department of Biology, Working Group Parasitology and Infection Biology, University of Koblenz, 56070 Koblenz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Lorenzo-Morales","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Enfermedades Tropicales y Salud P\u00fablica de Canarias, Universidad de La Laguna, Avda. Astrof\u00edsico Fco. S\u00e1nchez, S\/N, 38203 La Laguna, Spain"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Pediatr\u00eda, Medicina Preventiva y Salud P\u00fablica, Toxicolog\u00eda, Medicina Legal y Forense y Parasitolog\u00eda, Universidad de La Laguna, 38203 La Laguna, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6233-8224","authenticated-orcid":false,"given":"Jos\u00e9 E.","family":"Pi\u00f1ero","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Enfermedades Tropicales y Salud P\u00fablica de Canarias, Universidad de La Laguna, Avda. Astrof\u00edsico Fco. S\u00e1nchez, S\/N, 38203 La Laguna, Spain"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Pediatr\u00eda, Medicina Preventiva y Salud P\u00fablica, Toxicolog\u00eda, Medicina Legal y Forense y Parasitolog\u00eda, Universidad de La Laguna, 38203 La Laguna, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.medcli.2016.10.038","article-title":"Orally-Transmitted Chagas Disease","volume":"148","author":"Filigheddu","year":"2017","journal-title":"Med. 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