{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:13:19Z","timestamp":1790817199492,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2015,8,3]],"date-time":"2015-08-03T00:00:00Z","timestamp":1438560000000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BE1540\/11\u20102"],"award-info":[{"award-number":["BE1540\/11\u20102"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:p>Investigations regarding the chemistry and mechanism of action of 2\u2010methyl\u20101,4\u2010naphthoquinone (or menadione) derivatives revealed 3\u2010phenoxymethyl menadiones as a novel anti\u2010schistosomal chemical series. These newly synthesized compounds (<jats:bold>1<\/jats:bold>\u2013<jats:bold>7<\/jats:bold>) and their difluoromethylmenadione counterparts (<jats:bold>8<\/jats:bold>,<jats:bold> 9<\/jats:bold>) were found to be potent and specific inhibitors of <jats:italic>Schistosoma mansoni<\/jats:italic> thioredoxin\u2010glutathione reductase (<jats:italic>Sm<\/jats:italic><jats:styled-content style=\"fixed-case\">TGR<\/jats:styled-content>), which has been identified as a potential target for anti\u2010schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (<jats:italic>h<\/jats:italic><jats:styled-content style=\"fixed-case\">GR<\/jats:styled-content>) and selenium\u2010dependent human thioredoxin reductase (<jats:italic>h<\/jats:italic><jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>rxR), to evaluate the specificity of the inhibition. Structure\u2013activity relationships as well as physico\u2010 and electro\u2010chemical studies showed a high potential for the 3\u2010phenoxymethyl menadiones to inhibit <jats:italic>Sm<\/jats:italic><jats:styled-content style=\"fixed-case\">TGR<\/jats:styled-content> selectively compared to <jats:italic>h<\/jats:italic><jats:styled-content style=\"fixed-case\">GR<\/jats:styled-content> and <jats:italic>h<\/jats:italic><jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>rxR enzymes, in particular those bearing an \u03b1\u2010fluorophenol methyl ether moiety, which improves anti\u2010schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (<jats:bold>7<\/jats:bold>) displayed time\u2010dependent <jats:italic>Sm<\/jats:italic><jats:styled-content style=\"fixed-case\">TGR<\/jats:styled-content> inactivation, correlating with unproductive <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content>\u2010dependent redox cycling of <jats:italic>Sm<\/jats:italic><jats:styled-content style=\"fixed-case\">TGR<\/jats:styled-content>, and potent anti\u2010schistosomal action in worms cultured <jats:italic>ex\u00a0vivo<\/jats:italic>. In contrast, the difluoromethylmenadione analog <jats:bold>9<\/jats:bold>, which inactivates <jats:italic>Sm<\/jats:italic><jats:styled-content style=\"fixed-case\">TGR<\/jats:styled-content> through an irreversible non\u2010consuming <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content>\u2010dependent process, has little killing effect in worms cultured <jats:italic>ex\u00a0vivo<\/jats:italic>. Despite <jats:italic>ex\u00a0vivo<\/jats:italic> activity, none of the compounds tested was active <jats:italic>in\u00a0vivo<\/jats:italic>, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability.<\/jats:p>","DOI":"10.1111\/febs.13359","type":"journal-article","created":{"date-parts":[[2015,6,25]],"date-time":"2015-06-25T08:15:05Z","timestamp":1435220105000},"page":"3199-3217","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Synthesis and evaluation of 1,4\u2013naphthoquinone ether derivatives as <i>Sm<\/i><scp>TGR<\/scp> inhibitors and new anti\u2010schistosomal drugs"],"prefix":"10.1111","volume":"282","author":[{"given":"Laure","family":"Johann","sequence":"first","affiliation":[{"name":"UMR 7509 CNRS and University of Strasbourg European School of Chemistry, Polymers and Materials Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Belorgey","sequence":"additional","affiliation":[{"name":"UMR 7509 CNRS and University of Strasbourg European School of Chemistry, Polymers and Materials Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin\u2010Hung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Immunology\/Microbiology Rush University Medical Center Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latasha","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Immunology\/Microbiology Rush University Medical Center Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Chess\u00e9","sequence":"additional","affiliation":[{"name":"UMR 7509 CNRS and University of Strasbourg European School of Chemistry, Polymers and Materials Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Becker","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Interdisciplinary Research Center Justus Liebig University of Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Immunology\/Microbiology Rush University Medical Center Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Davioud\u2010Charvet","sequence":"additional","affiliation":[{"name":"UMR 7509 CNRS and University of Strasbourg European School of Chemistry, Polymers and Materials Strasbourg 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