{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:01:06Z","timestamp":1789682466503,"version":"4.0.1"},"reference-count":58,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:00:00Z","timestamp":1729036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo, ANID, project Fondecyt Iniciaci\u00f3n N\u00b0","award":["11240973"],"award-info":[{"award-number":["11240973"]}]},{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo, ANID, project Fondecyt Iniciaci\u00f3n N\u00b0","award":["11220310"],"award-info":[{"award-number":["11220310"]}]},{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo, ANID, project Fondecyt Iniciaci\u00f3n N\u00b0","award":["1230644"],"award-info":[{"award-number":["1230644"]}]},{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo, ANID, project Fondecyt Iniciaci\u00f3n N\u00b0","award":["EQM230118"],"award-info":[{"award-number":["EQM230118"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chagas disease is a prevalent health problem in Latin America which has received insufficient attention worldwide. Current treatments for this disease, benznidazole and nifurtimox, have limited efficacy and may cause side effects. A recent study proposed investigating a wide range of nitroindazole and indazolone derivatives as feasible treatments. Therefore, it is proposed that adding a nitro group at the 5-position of the indazole and indazolone structure could enhance trypanocidal activity by inducing oxidative stress through activation of the nitro group by NTRs (nitroreductases). The study results indicate that the nitro group advances free radical production, as confirmed by several analyses. Compound 5a (5-nitro-2-picolyl-indazolin-3-one) shows the most favorable trypanocidal activity (1.1 \u00b1 0.3 \u00b5M in epimastigotes and 5.4 \u00b1 1.0 \u00b5M in trypomastigotes), with a selectivity index superior to nifurtimox. Analysis of the mechanism of action indicated that the nitro group at the 5-position of the indazole ring induces the generation of reactive oxygen species (ROS), which causes apoptosis in the parasites. Computational docking studies reveal how the compounds interact with critical residues of the NTR and FMNH2 (flavin mononucleotide reduced) in the binding site, which is also present in active ligands. The lipophilicity of the studied series was shown to influence their activity, and the nitro group was found to play a crucial role in generating free radicals. Further investigations are needed of derivatives with comparable lipophilic characteristics and the location of the nitro group in different positions of the base structure.<\/jats:p>","DOI":"10.3390\/ijms252011107","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T07:58:32Z","timestamp":1729065512000},"page":"11107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi"],"prefix":"10.3390","volume":"25","author":[{"given":"Josu\u00e9","family":"Pozo-Mart\u00ednez","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Clinical, Faculty of Medicine, University of Chile, Santiago 8380453, Chile"},{"name":"Laboratorio de Qu\u00edmica-M\u00e9dica, Facultad de Ciencia y Tecnolog\u00eda, Universidad del Azuay, Av. 24 de Mayo 777, Cuenca 010204, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3390-7157","authenticated-orcid":false,"given":"Vicente J.","family":"Ara\u0301n","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2448-9376","authenticated-orcid":false,"given":"Mat\u00edas","family":"Z\u00fa\u00f1iga-Bustos","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Universidad Tecnol\u00f3gica Metropolitana, Santiago 8940577, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebasti\u00e1n","family":"Parra-Magna","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Universidad Tecnol\u00f3gica Metropolitana, Santiago 8940577, Chile"},{"name":"Free Radical and Antioxidants Laboratory, Inorganic and Analytical Department, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban","family":"Rocha-Valderrama","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Universidad Tecnol\u00f3gica Metropolitana, Santiago 8940577, Chile"},{"name":"Free Radical and Antioxidants Laboratory, Inorganic and Analytical Department, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3200-9811","authenticated-orcid":false,"given":"Ana","family":"Liempi","sequence":"additional","affiliation":[{"name":"Programa de Biolog\u00eda Integrativa, Instituto de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8710-6745","authenticated-orcid":false,"given":"Christian","family":"Castillo","sequence":"additional","affiliation":[{"name":"Programa de Biolog\u00eda Integrativa, Instituto de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Olea-Azar","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Clinical, Faculty of Medicine, University of Chile, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1733-9126","authenticated-orcid":false,"given":"Mauricio","family":"Moncada-Basualto","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Universidad Tecnol\u00f3gica Metropolitana, Santiago 8940577, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lidani, K.C.F., Andrade, F.A., Bavia, L., Damasceno, F.S., Beltrame, M.H., Messias-Reason, I.J., and Sandri, T.L. 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