{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:53:30Z","timestamp":1784202810922,"version":"3.55.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["Finance Code 001"],"award-info":[{"award-number":["Finance Code 001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006507","name":"Funda\u00e7\u00e3o Oswaldo Cruz","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006507","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Chagas disease is a neglected illness caused by <jats:italic>Trypanosoma cruzi<\/jats:italic> and its treatment is done only with two drugs, nifurtimox and benznidazole. However, both drugs are ineffective in the chronic phase, in addition to causing serious side effects. This context of therapeutic limitation justifies the continuous research for alternative drugs. Here, we study the <jats:italic>in vitro<\/jats:italic> trypanocidal effects of the non-steroidal anti-inflammatory drug nimesulide, a molecule that has in its chemical structure a toxicophoric nitroaromatic group (NO<jats:sub>2<\/jats:sub>). The set of results obtained in this work highlights the potential for repurposing nimesulide in the treatment of this disease that affects millions of people around the world.<\/jats:p>","DOI":"10.1371\/journal.pone.0258292","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T17:21:31Z","timestamp":1634923291000},"page":"e0258292","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Drug repurposing for Chagas disease: In vitro assessment of nimesulide against Trypanosoma cruzi and insights on its mechanisms of action"],"prefix":"10.1371","volume":"16","author":[{"given":"Joana D\u2019Arc S.","family":"Trindade","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9lio Geraldo","family":"Freire-de-Lima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"C\u00f4rte-Real","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Decote-Ricardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0563-3483","authenticated-orcid":true,"given":"Marco Edilson","family":"Freire de Lima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"pone.0258292.ref001","unstructured":"World Health Organization, Chagas disease. 2020; https:\/\/www.who.int\/topics\/chagas_disease\/en\/"},{"key":"pone.0258292.ref002","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s40249-015-0092-7","article-title":"Preventing the transmission of American trypanosomiasis and its spread into non-endemic countries","volume":"4","author":"Q Liu","year":"2015","journal-title":"Infect Dis Poverty"},{"key":"pone.0258292.ref003","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.amjmed.2013.12.017","article-title":"Free-roaming kissing bugs, vectors of Chagas disease, feed often on humans in the Southwest","volume":"127","author":"S A Klotz","year":"2014","journal-title":"Am J Med"},{"key":"pone.0258292.ref004","first-page":"57","article-title":"Estresse e resili\u00eancia em doen\u00e7a de Chagas","volume":"24","author":"DCG D\u2019Arce Mota","year":"2006","journal-title":"Aletheia"},{"key":"pone.0258292.ref005","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: identifying and developing new uses for existing drugs","volume":"3","author":"TT Ashburn","year":"2004","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0258292.ref006","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: progress, challenges, and recommendations","volume":"18","author":"S Pushpakom","year":"2018","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0258292.ref007","doi-asserted-by":"crossref","first-page":"e2844","DOI":"10.1371\/journal.pntd.0002844","article-title":"Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics","volume":"8","author":"A Trochine","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"key":"pone.0258292.ref008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-12-385895-5.00001-3","article-title":"Bioactive lipids in Trypanosoma cruzi infection","volume":"76","author":"FS Machado","year":"2011","journal-title":"Adv Parasitol"},{"issue":"6766","key":"pone.0258292.ref009","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/35003208","article-title":"Uptake of apoptotic cells drives the growth of a pathogenic tripanosome in macrophages","volume":"403","author":"CG Freire-de-Lima","year":"2000","journal-title":"Nature"},{"key":"pone.0258292.ref010","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.bmcl.2016.12.030","article-title":"1,2,3-triazole-nimesulide hybrid: their design, synthesis, and evaluation as potential anticancer agents","volume":"3","author":"J Mareddy","year":"2017","journal-title":"Bioorg Med Chem"},{"key":"pone.0258292.ref011","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3390\/biom9090437","article-title":"Synthesis and different effects of biotinylated PAMAM G3 dendrimer substituted with nimesulide in human normal fibroblasts and squamous carcinoma cells","volume":"9","author":"L Uram","year":"2019","journal-title":"Biomolecules"},{"key":"pone.0258292.ref012","doi-asserted-by":"crossref","first-page":"e0190509","DOI":"10.1371\/journal.pone.0190509","article-title":"Drug repurposing: in-vitro anti-glycation properties of 18 common drugs","volume":"13","author":"S Rasheed","year":"2018","journal-title":"PLoS ONE"},{"issue":"1","key":"pone.0258292.ref013","doi-asserted-by":"crossref","first-page":"69","DOI":"10.5334\/gh.891","article-title":"COVID-19: implications for people with Chagas Disease","volume":"15","author":"EJ Zaidel","year":"2020","journal-title":"Glob Heart"},{"key":"pone.0258292.ref014","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0008-6363(03)00361-4","article-title":"Pathophysiology of the heart in Chagas\u2019 disease: current status and new developments","volume":"60","author":"ML Higuchi","year":"2003","journal-title":"Cardiovasc Res"},{"key":"pone.0258292.ref015","doi-asserted-by":"crossref","first-page":"246","DOI":"10.2174\/138945009787581168","article-title":"Electron microscopy in antiparasitic chemotherapy: A (close) view to a kill","volume":"10","author":"MA Vannier-Santos","year":"2009","journal-title":"Curr Drug Targets"},{"key":"pone.0258292.ref016","doi-asserted-by":"crossref","first-page":"925","DOI":"10.2174\/138161208784041033","article-title":"Ultrastructural alterations in organelles of parasitic protozoa induced by different classes of metabolic inhibitors","volume":"14","author":"JCF Rodrigues","year":"2008","journal-title":"Curr Pharm Des"},{"key":"pone.0258292.ref017","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.micron.2008.08.003","article-title":"Different cell death pathways induced by drugs in Trypanosoma cruzi: An ultrastructural study","volume":"40","author":"RFS Menna-Barreto","year":"2009","journal-title":"J Micron"},{"key":"pone.0258292.ref018","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/0014-4894(77)90071-6","article-title":"Trypanosoma cruzi: ultrastructural and metabolic alterations of epimastigotes by beta-lapachone","volume":"42","author":"R Docampo","year":"1977","journal-title":"Exp Parasitol"},{"issue":"8","key":"pone.0258292.ref019","first-page":"1236","article-title":"Contextualizing acid-base reactions according to Bronsted-Lowry protonic theory using propranolol and nimesulide tablets","volume":"36","author":"AA Gonsalves","year":"2013","journal-title":"Quim Nova"},{"key":"pone.0258292.ref020","first-page":"197","volume-title":"Analytical Profiles of Drugs Substances and Excipients","author":"A Singh","year":"2001"},{"key":"pone.0258292.ref021","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.molstruc.2017.12.085","article-title":"The nitro-reduced metabolite of nimesulide: crystal structure, spectroscopic characterization, ESI-QTOF mass spectrometric analysis and antibacterial evaluation","volume":"1157","author":"JHB Nunes","year":"2018","journal-title":"Journal of Molecular Structure"},{"key":"pone.0258292.ref022","doi-asserted-by":"crossref","first-page":"6517","DOI":"10.1016\/j.bmc.2009.08.009","article-title":"Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole","volume":"17","author":"RC Maia","year":"2009","journal-title":"Bioorg Med Chem"},{"key":"pone.0258292.ref023","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1590\/S0103-50532007000200021","article-title":"Chemical modifications of nimesulide","volume":"18","author":"S Pericherla","year":"2007","journal-title":"J Braz Chem Soc"},{"key":"pone.0258292.ref024","first-page":"184","volume-title":"Doen\u00e7a de Chagas: manual para experimenta\u00e7\u00e3o animal","author":"HS Barbosa","year":"2000"},{"key":"pone.0258292.ref025","first-page":"305","volume-title":"Assay Guidance Manual","author":"TL Riss","year":"2013"},{"key":"pone.0258292.ref026","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0022-1759(91)90114-U","article-title":"An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT","volume":"142","author":"NW Roehm","year":"1991","journal-title":"J Immunol Meth"},{"key":"pone.0258292.ref027","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/PL00008532","article-title":"Setting of a colorimetric method to determine the viability of Trypanosoma cruzi epimastigotes","volume":"86","author":"S Muelas-Serrano","year":"2000","journal-title":"Parasitol Res"},{"key":"pone.0258292.ref028","first-page":"642","article-title":"A critical review on Chagas disease chemotherapy","volume":"106","author":"JR Coura","year":"2011","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"pone.0258292.ref029","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1080\/14756366.2019.1626375","article-title":"Appraisal of anti-protozoan activity of nitroaromatic benzenesulfonamides inhibiting carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani","volume":"34","author":"A Nocentini","year":"2019","journal-title":"J Enzyme Inhib Med Chem"},{"key":"pone.0258292.ref030","doi-asserted-by":"crossref","first-page":"4454","DOI":"10.2174\/0929867325666180426164352","article-title":"Current and future prospects of nitro-compounds as drugs for Trypanosomiasis and Leishmaniasis","volume":"26","author":"S Patterson","year":"2019","journal-title":"Curr Med Chem"},{"key":"pone.0258292.ref031","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/minf.201100023","article-title":"Association drugs, targets and clinical outcomes into an integrated network affords a new platform for computer-aided drug repurposing","volume":"30","author":"TI Oprea","year":"2011","journal-title":"Mol Inform"},{"key":"pone.0258292.ref032","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.freeradbiomed.2005.05.013","article-title":"Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro","volume":"39","author":"VKS Tay","year":"2005","journal-title":"Free Radic Biol Med"},{"key":"pone.0258292.ref033","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0006-291X(03)00618-1","article-title":"Mitochondrial permeability transition: a common pathway to necrosis and apoptosis","volume":"304","author":"JS Kim","year":"2003","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0258292.ref034","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s10495-006-0525-7","article-title":"Role of the mitochondrial membrane permeability transition in cell death","volume":"12","author":"Y Tsujimoto","year":"2007","journal-title":"Apoptosis"},{"key":"pone.0258292.ref035","first-page":"614014","article-title":"The double-edged sword in pathogenic Trypanosomatids: the pivotal role of mitochondria in oxidative stress and bioenergetics","author":"RFS Menna-Barreto","year":"2014","journal-title":"Biomed Res Int"},{"key":"pone.0258292.ref036","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1590\/S0074-02762008000400001","article-title":"Electron microscopy of trypanosomes: A historical review","volume":"103","author":"W de Souza","year":"2008","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"pone.0258292.ref037","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1590\/S0001-37652008000100011","article-title":"Active transcription and ultrastructural changes during Trypanosoma cruzi metacyclogenesis","volume":"80","author":"LRP Ferreira","year":"2008","journal-title":"Ann Braz Acad Scienc"},{"issue":"6","key":"pone.0258292.ref038","doi-asserted-by":"crossref","first-page":"510","DOI":"10.2174\/156652408785748004","article-title":"Chagas heart disease pathogenesis: one mechanism or many?","volume":"8","author":"KM Bonney","year":"2008","journal-title":"Curr Mol Med"},{"key":"pone.0258292.ref039","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1021\/acsinfecdis.8b00253","article-title":"Successful aspects of the coadministration of sterol 14\u03b1-demethylase inhibitor VFV and benznidazole in experimental mouse models of Chagas disease caused by the drug-resistant strain of Trypanosome cruzi","volume":"5","author":"FH Guedes-da-Silva","year":"2019","journal-title":"ACS Infec Dis"},{"key":"pone.0258292.ref040","doi-asserted-by":"crossref","first-page":"e111778","DOI":"10.1016\/j.ejmech.2019.111778","article-title":"Combined therapy with Benznidazole and repurposed drugs Clofazimine and Benidipine for chronic Chagas disease","volume":"184","author":"ML Sbaraglini","year":"2019","journal-title":"Eur. J. Med. Chem"},{"key":"pone.0258292.ref041","article-title":"New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomized trial","author":"F Torrico","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"pone.0258292.ref042","first-page":"30","article-title":"Nimesulide and hepatic adverse effects: roles of reactive metabolites and host factors","volume":"128","author":"UA Boelsterli","year":"2002","journal-title":"International Journal of Clinical practice. Supplement"},{"key":"pone.0258292.ref043","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1093\/chromsci\/bms014","article-title":"Quantification of nimesulide in human plasma by high-performance liquid chrommatography with ultraviolet detector (HPLC-UV): application to pharmacokinetic studies in 28 healthy Korean subjects","volume":"50","author":"MS Kim","year":"2012","journal-title":"J Chromatogr Sci"},{"key":"pone.0258292.ref044","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/3-7643-7410-1_2","volume-title":"Nimesulide\u2013Actions and Uses","author":"A Bernareggi","year":"2005"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258292","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T17:22:08Z","timestamp":1634923328000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258292"}},"subtitle":[],"editor":[{"given":"Moustafa Elsayed","family":"El-Araby","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,22]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0258292","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,22]]}}}