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The most potent representatives, called schistodiones, exhibited IC50 values &amp;lt;5 \u03bcM against larvae and ex vivoSchistosoma mansoni adult worms and moderate activity per os in the S. mansoni-infected mouse model in vivo. We synthesized the putative 3-benzoylmenadione metabolites of the most active compounds and explored the possible mode(s) of action using the yeast model and the recombinant drug target S.\u00a0mansoni thioredoxin-glutathione reductase. Two drug targets were identified in yeast: the yeast NADH dehydrogenase and Cox15, involved in events responsible for respiratory growth defect in yeast, respectively: (i) the bioreductive activation step producing reactive oxygen species and (ii) the heme a synthase inhibition. These two drug targets are discussed in the context of S.mansoni biology, with S. mansoni thioredoxin\u2013glutathione reductase redox-cycling and a potential source of oxidative stress in the parasite.<\/jats:p>","DOI":"10.1021\/acsomega.6c06911","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:02:17Z","timestamp":1790690537000},"page":"61479-61495","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Antischistosomal\nActivity Profile of\nSeveral Sub-Series of Redox-Active Lead 3-Benzylmenadiones\u2500Investigations\nof the Modes of Action in Yeast"],"prefix":"10.1021","volume":"11","author":[{"given":"Jeremy","family":"Pecourneau","sequence":"first","affiliation":[{"name":"UMR7042 CNRS-Universite\u0301 de Strasbourg-Universite\u0301 Haute-Alsace, European School of Chemistry, Polymers and Materials (ECPM) , , 25, rue Becquerel , ,","place":["Strasbourg, France, F-67087"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Richard","sequence":"additional","affiliation":[{"name":"UMR7042 CNRS-Universite\u0301 de Strasbourg-Universite\u0301 Haute-Alsace, European School of Chemistry, Polymers and Materials (ECPM) , , 25, rue Becquerel , ,","place":["Strasbourg, France, F-67087"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Meunier","sequence":"additional","affiliation":[{"name":"Universite\u0301 Paris-Saclay , , ,","place":["Gif-sur-Yvette, France, F-91198 Cedex"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maude","family":"Dagenais","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute , Kreuzstrasse 2 , ,","place":["Allschwil, Switzerland, CH-4123"]},{"name":"University of Basel , Petersgraben 1 , ,","place":["Basel, Switzerland, CH-4001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce\u0301cile","family":"Ha\u0308berli","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute , Kreuzstrasse 2 , ,","place":["Allschwil, Switzerland, CH-4123"]},{"name":"University of Basel , Petersgraben 1 , ,","place":["Basel, Switzerland, CH-4001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6815-4909","authenticated-orcid":true,"given":"David L.","family":"Williams","sequence":"additional","affiliation":[{"name":"Rush University Medical Center , , 1735 West Harrison Street , , ,","place":["Chicago, Illinois, United States, 60612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Keiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute , Kreuzstrasse 2 , ,","place":["Allschwil, Switzerland, CH-4123"]},{"name":"University of Basel , Petersgraben 1 , ,","place":["Basel, Switzerland, CH-4001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-4034","authenticated-orcid":true,"given":"Elisabeth","family":"Davioud-Charvet","sequence":"additional","affiliation":[{"name":"UMR7042 CNRS-Universite\u0301 de Strasbourg-Universite\u0301 Haute-Alsace, European School of Chemistry, Polymers and Materials (ECPM) , , 25, rue Becquerel , ,","place":["Strasbourg, France, F-67087"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"2026101315080633800_cit1","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1556\/1886.2024.00013","article-title":"Insights into the epidemiology, pathogenesis,\nand differential diagnosis of schistosomiasis","volume":"14","author":"Ponzo","year":"2024","journal-title":"Eur. 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