{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:24:29Z","timestamp":1787073869205,"version":"build-2736575974"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"25","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006507","name":"Funda????o Oswaldo Cruz","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006507","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient??fico e Tecnol??gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda????o Carlos Chagas Filho de Amparo ?? Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Visceral leishmaniasis, caused by the parasite Leishmania infantum, is a life-threatening disease with limited therapeutic options that are often associated with toxicity and resistance. In this study, we investigated the in vitro leishmanicidal effects of silibinin, a key flavonolignan from Silybum marianum, against both the promastigote and intracellular amastigote forms of L. infantum. Mechanistically, silibinin inhibits trypanothione reductase (TR), disrupting the redox balance in the parasite and causing cell death. Silibinin concentration-dependently inhibited promastigote proliferation (IC50 of 416.7 \u03bcM) with potent activity against intracellular amastigotes (EC50 of 0.7 \u03bcM) and a high selectivity index (242), indicating its strong therapeutic potential and nontoxicity to macrophages. Importantly, silibinin disrupts the L. infantum redox balance by inhibiting TR activity, which increases the reactive oxygen species (ROS) levels to kill the parasite. ROS accumulation and the inhibition of parasite proliferation were significantly correlated (Pearson correlation coefficient of 0.9895). Molecular docking confirmed that silibinin binds to the catalytic site of TR, corroborating its role in ROS-mediated parasite death. Furthermore, in silico ADMET analysis revealed that silibinin has favorable pharmacokinetic properties for oral administration. Finally, in vitro and in silico studies indicated that silibinin inhibits TR, a key enzyme in Leishmania redox homeostasis, to exert antileishmanial effects.<\/jats:p>","DOI":"10.1021\/acsomega.5c02606","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T15:31:22Z","timestamp":1750260682000},"page":"27262-27271","source":"Crossref","is-referenced-by-count":1,"title":["<i>In Vitro<\/i>\n                    Leishmanicidal Effect of\nSilibinin: Disrupting Redox Balance via Trypanothione Reductase Inhibition"],"prefix":"10.1021","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9056-9636","authenticated-orcid":true,"given":"Natalia","family":"Debize da Motta","sequence":"first","affiliation":[{"name":"Instituto Oswaldo Cruz\/Fundac\u0327a\u0303o Oswaldo Cruz , , ,","place":["Rio de Janeiro, Brazil, 21040-360"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiza","family":"Gervazoni Ferreira de Oliveira","sequence":"additional","affiliation":[{"name":"Instituto Oswaldo Cruz\/Fundac\u0327a\u0303o Oswaldo Cruz , , ,","place":["Rio de Janeiro, Brazil, 21040-360"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myslene","family":"Soares da Fonseca","sequence":"additional","affiliation":[{"name":"Instituto Oswaldo Cruz\/Fundac\u0327a\u0303o Oswaldo Cruz , , ,","place":["Rio de Janeiro, Brazil, 21040-360"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Job","family":"Domingos Inacio Filho","sequence":"additional","affiliation":[{"name":"Instituto Oswaldo Cruz\/Fundac\u0327a\u0303o Oswaldo Cruz , , ,","place":["Rio de Janeiro, Brazil, 21040-360"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1363-3176","authenticated-orcid":true,"given":"Elmo Eduardo","family":"de Almeida-Amaral","sequence":"additional","affiliation":[{"name":"Instituto Oswaldo Cruz\/Fundac\u0327a\u0303o Oswaldo Cruz , , ,","place":["Rio de Janeiro, Brazil, 21040-360"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"2026081811283942900_cit1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3390\/pharmacy12010030","article-title":"Review of\nLeishmaniasis Treatment: Can We See the Forest\nthrough the Trees?","volume":"12","author":"Shmueli","year":"2024","journal-title":"Pharmacy"},{"issue":"10151","key":"2026081811283942900_cit2","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"2026081811283942900_cit3","author":"Pan American Health Organization","year":"2022","journal-title":"Guideline for the\ntreatment of leishmaniasis in the Americas"},{"key":"2026081811283942900_cit4","unstructured":"DNDI\n          \n          Portifolio\nDNDI\n          2015\n          http:\/\/www.dndi.org\/diseases-projects\/portfolio\/"},{"key":"2026081811283942900_cit5","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.3389\/fchem.2020.579891","article-title":"Use of\nNatural Products in Leishmaniasis Chemotherapy: An Overview","volume":"8","author":"Gervazoni","year":"2020","journal-title":"Frontiers in Chemistry"},{"issue":"7","key":"2026081811283942900_cit6","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.3390\/molecules23071560","article-title":"In-Vitro\nActivity of Silybin and Related flavonolignans against Leishmania\ninfantum and L. donovani","volume":"23","author":"Olias-Molero","year":"2018","journal-title":"Molecules"},{"issue":"9","key":"2026081811283942900_cit7","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1039\/C3NP70122K","article-title":"Chemistry\nof silybin","volume":"31","author":"Biedermann","year":"2014","journal-title":"Nat. Prod Rep"},{"key":"2026081811283942900_cit8","doi-asserted-by":"publisher","first-page":"2202","DOI":"10.1002\/ptr.6171","article-title":"Milk thistle (Silybum\nmarianum): A concise overview\non its chemistry, pharmacological, and nutraceutical uses in liver\ndiseases","volume":"32","author":"Abenavoli","year":"2018","journal-title":"Phytother. Res."},{"issue":"1","key":"2026081811283942900_cit9","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/mc.22253","article-title":"Silibinin and its 2,3-dehydro-derivative\ninhibit basal cell carcinoma growth via suppression of mitogenic signaling\nand transcription factors activation","volume":"55","author":"Tilley","year":"2016","journal-title":"Mol. Carcinog"},{"issue":"1","key":"2026081811283942900_cit10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.17420\/ap6401.129","article-title":"Investigating in vitro\nanti-leishmanial effects of silibinin and silymarin on Leishmania\nmajor","volume":"64","author":"Faridnia","year":"2018","journal-title":"Ann. Parasitol."},{"key":"2026081811283942900_cit11","doi-asserted-by":"publisher","first-page":"345","DOI":"10.18632\/oncotarget.28587","article-title":"The importance of integrated\ntherapies on cancer: Silibinin, an old\nand new molecule","volume":"15","author":"Roca","year":"2024","journal-title":"Oncotarget"},{"issue":"9","key":"2026081811283942900_cit12","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/nrd1824","article-title":"Opportunities and challenges\nin antiparasitic drug discovery","volume":"4","author":"Pink","year":"2005","journal-title":"Nat. Rev. Drug\nDiscov"},{"key":"2026081811283942900_cit13","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.ejmech.2017.08.055","article-title":"Efficacy of a series\nof alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma\ncruzi","volume":"139","author":"Tempone","year":"2017","journal-title":"European journal of medicinal chemistry"},{"issue":"Pt 3","key":"2026081811283942900_cit14","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.foodres.2017.07.017","article-title":"The silymarin\ncomposition\u00b7\u00b7\u00b7 and why does it matter???","volume":"100","author":"Chambers","year":"2017","journal-title":"Food Res. Int."},{"issue":"3","key":"2026081811283942900_cit15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004918","article-title":"HIV aspartyl peptidase\ninhibitors interfere with cellular proliferation, ultrastructure and\nmacrophage infection of Leishmania amazonensis","volume":"4","author":"Santos","year":"2009","journal-title":"PLoS One"},{"issue":"9","key":"2026081811283942900_cit16","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1086\/592280","article-title":"Intracellular survival of Leishmania\nspecies that cause\nvisceral leishmaniasis is significantly reduced by HIV-1 protease\ninhibitors","volume":"198","author":"Trudel","year":"2008","journal-title":"J. Infect Dis"},{"issue":"9","key":"2026081811283942900_cit17","doi-asserted-by":"publisher","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM:\nPredicting Small-Molecule\nPharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"issue":"1\u20133","key":"2026081811283942900_cit18","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and\ncomputational approaches to estimate solubility and permeability in\ndrug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv.\nDrug Deliv Rev."},{"issue":"4","key":"2026081811283942900_cit19","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and\ndrug-like compounds: the rule-of-five revolution","volume":"1","author":"Lipinski","year":"2004","journal-title":"Drug Discov Today Technol."},{"key":"2026081811283942900_cit20","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.640561","article-title":"Epigallocathechin-O-3-Gallate\nInhibits Trypanothione\nReductase of Leishmania infantum, Causing Alterations in Redox Balance\nand Leading to Parasite Death","volume":"11","author":"Inacio","year":"2021","journal-title":"Front Cell Infect\nMicrobiol"},{"issue":"8","key":"2026081811283942900_cit21","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1021\/np400193m","article-title":"Reactive\noxygen species production by quercetin causes the death of Leishmania\namazonensis intracellular amastigotes","volume":"76","author":"Fonseca-Silva","year":"2013","journal-title":"J. Nat.\nProd"},{"issue":"8","key":"2026081811283942900_cit22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003093","article-title":"The effect\nof (\u2212)-epigallocatechin 3-O\u2013gallate in vitro and in\nvivo in Leishmania braziliensis: involvement of reactive oxygen species\nas a mechanism of action","volume":"8","author":"Inacio","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"issue":"2","key":"2026081811283942900_cit23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014666","article-title":"Reactive\noxygen species production and mitochondrial dysfunction contribute\nto quercetin induced death in Leishmania amazonensis","volume":"6","author":"Fonseca-Silva","year":"2011","journal-title":"PLoS One"},{"issue":"2","key":"2026081811283942900_cit24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004442","article-title":"Oral Efficacy of Apigenin against\nCutaneous Leishmaniasis:\nInvolvement of Reactive Oxygen Species and Autophagy as a Mechanism\nof Action","volume":"10","author":"Fonseca-Silva","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"issue":"4","key":"2026081811283942900_cit25","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1021\/acs.jnatprod.5b00011","article-title":"Effect\nof Apigenin on Leishmania amazonensis Is Associated with Reactive\nOxygen Species Production Followed by Mitochondrial Dysfunction","volume":"78","author":"Fonseca-Silva","year":"2015","journal-title":"J. Nat. Prod"},{"issue":"1\u20132","key":"2026081811283942900_cit26","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.molbiopara.2015.11.003","article-title":"Thiol redox biology of trypanosomatids\nand potential\ntargets for chemotherapy","volume":"206","author":"Leroux","year":"2016","journal-title":"Mol. Biochem. Parasitol."},{"issue":"10","key":"2026081811283942900_cit27","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1093\/emboj\/16.10.2590","article-title":"Disruption\nof the trypanothione reductase gene of Leishmania decreases its ability\nto survive oxidative stress in macrophages","volume":"16","author":"Dumas","year":"1997","journal-title":"EMBO J."},{"issue":"2","key":"2026081811283942900_cit28","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1046\/j.1365-2958.1998.00968.x","article-title":"Evidence\nthat trypanothione\nreductase is an essential enzyme in Leishmania by targeted replacement\nof the tryA gene locus","volume":"29","author":"Tovar","year":"1998","journal-title":"Mol. Microbiol."},{"issue":"4","key":"2026081811283942900_cit29","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1515\/BC.2003.062","article-title":"The parasite-specific trypanothione\nmetabolism of trypanosoma and leishmania","volume":"384","author":"Krauth-Siegel","year":"2003","journal-title":"Biol.\nChem."},{"key":"2026081811283942900_cit30","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.2174\/0929867311320210005","article-title":"Trypanosomatidae\ndiseases: from the\ncurrent therapy to the efficacious role of trypanothione reductase\nin drug discovery","volume":"20","author":"Bernardes","year":"2013","journal-title":"In Curr. Med. Chem."},{"key":"2026081811283942900_cit31","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1002\/cmdc.201300176","article-title":"Inhibition\nof Leishmania infantum trypanothione reductase\nby azole-based compounds: A comparative analysis with its physiological\nsubstrate by x-ray crystallography","volume":"8","author":"Baiocco","year":"2013","journal-title":"ChemMedChem."},{"key":"2026081811283942900_cit32","doi-asserted-by":"publisher","first-page":"1861","DOI":"10.4155\/fmc.13.146","article-title":"Structural\ninsights into the enzymes\nof the trypanothione pathway: Targets for antileishmaniasis drugs","volume":"5","author":"Colotti","year":"2013","journal-title":"Future Medicinal Chemistry"},{"issue":"16","key":"2026081811283942900_cit33","doi-asserted-by":"publisher","first-page":"3148","DOI":"10.1021\/jm000156+","article-title":"Use of an additional hydrophobic\nbinding site, the\nZ site, in the rational drug design of a new class of stronger trypanothione\nreductase inhibitor, quaternary alkylammonium phenothiazines","volume":"43","author":"Khan","year":"2000","journal-title":"J. Med. Chem."},{"issue":"13","key":"2026081811283942900_cit34","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.1002\/jcc.21538","article-title":"Molecular\ndocking studies of selected\ntricyclic and quinone derivatives on trypanothione reductase of Leishmania\ninfantum","volume":"31","author":"Venkatesan","year":"2010","journal-title":"J. Comput. Chem."},{"issue":"1","key":"2026081811283942900_cit35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005281","article-title":"Cyclobenzaprine Raises\nROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected\nMice","volume":"11","author":"Cunha-Junior","year":"2017","journal-title":"PLoS neglected tropical diseases"},{"issue":"1","key":"2026081811283942900_cit36","doi-asserted-by":"publisher","first-page":"20440","DOI":"10.1038\/s41598-020-77066-2","article-title":"Bioassay-based\nCorchorus capsularis L. leaf-derived beta-sitosterol exerts antileishmanial\neffects against Leishmania donovani by targeting trypanothione reductase","volume":"10","author":"Pramanik","year":"2020","journal-title":"Sci. Rep"},{"issue":"9","key":"2026081811283942900_cit37","doi-asserted-by":"publisher","first-page":"2664","DOI":"10.1021\/acs.jnatprod.9b00632","article-title":"(\u2212)-Epigallocatechin\n3-O-Gallate\nas a New Approach for the Treatment of Visceral Leishmaniasis","volume":"82","author":"Inacio","year":"2019","journal-title":"J. Nat. Prod."},{"key":"2026081811283942900_cit38","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate\npharmacokinetics, drug-likeness and medicinal chemistry friendliness\nof small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"issue":"Pt 3","key":"2026081811283942900_cit39","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1042\/bj20021298","article-title":"Ellman\u2019s-reagent-mediated\nregeneration of trypanothione in situ: substrate-economical microplate\nand time-dependent inhibition assays for trypanothione reductase","volume":"369","author":"Hamilton","year":"2003","journal-title":"Biochem. J."},{"issue":"8","key":"2026081811283942900_cit40","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1002\/cmdc.200900097","article-title":"Improved tricyclic inhibitors of trypanothione reductase\nby screening and chemical synthesis","volume":"4","author":"Richardson","year":"2009","journal-title":"ChemMedChem."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.5c02606","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/10\/25\/27262\/40839431\/ao5c02606.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/10\/25\/27262\/40839431\/ao5c02606.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:26:27Z","timestamp":1787070387000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/10\/25\/27262\/3654803\/In-Vitro-Leishmanicidal-Effect-of-Silibinin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":40,"journal-issue":{"issue":"25","published-online":{"date-parts":[[2025,6,18]]},"published-print":{"date-parts":[[2025,7,1]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.5c02606","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]}}}