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Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme\u2010inhibition profiles, including eight HDAC8 inhibitors with &gt;10\u2010fold selectivity in comparable functional inhibition assays and IC<jats:sub>50<\/jats:sub> values against HDAC8&lt;100\u2005nM. HDAC8\u2010selective inhibitors showed the lowest potency against <jats:italic>Schistosoma mansoni<\/jats:italic> newly transformed schistosomula (NTS). Pan\u2010HDAC inhibitors <jats:bold>MMH258<\/jats:bold>, <jats:bold>MMH259<\/jats:bold>, and <jats:bold>MMH373<\/jats:bold>, as assessed by functional inhibition assays, with minimal or no\u2010observed hHDAC8 and SmHDAC8 activities, were active against both NTS (<jats:bold>MMH258<\/jats:bold>, IC<jats:sub>50<\/jats:sub>=1.5\u2005\u03bcM; <jats:bold>MMH259<\/jats:bold>, IC<jats:sub>50<\/jats:sub>=2.3\u2005\u03bcM) and adult <jats:italic>S. mansoni<\/jats:italic> (<jats:bold>MMH258<\/jats:bold>, IC<jats:sub>50<\/jats:sub>=2.1\u2005\u03bcM; <jats:bold>MMH373<\/jats:bold>, IC<jats:sub>50<\/jats:sub>=3.4\u2005\u03bcM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult <jats:italic>S. mansoni<\/jats:italic> activities.<\/jats:p>","DOI":"10.1002\/cmdc.202100622","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T06:58:24Z","timestamp":1660892304000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against <i>Schistosoma mansoni<\/i>"],"prefix":"10.1002","volume":"17","author":[{"given":"Muhammad Murtaza","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Chemical and Physical Sciences University of Toronto Mississauga  3359 Mississauga Road North Mississauga ON L5L 1C6 Canada"},{"name":"Department of Chemistry University of Toronto  80 St. George Street Toronto ON M5S 3H6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abootaleb","family":"Sedighi","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences University of Toronto Mississauga  3359 Mississauga Road North Mississauga ON L5L 1C6 Canada"},{"name":"Department of Chemistry University of Toronto  80 St. George Street Toronto ON M5S 3H6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olasunkanmi O.","family":"Olaoye","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences University of Toronto Mississauga  3359 Mississauga Road North Mississauga ON L5L 1C6 Canada"},{"name":"Department of Chemistry University of Toronto  80 St. George Street Toronto ON M5S 3H6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9cile","family":"H\u00e4berli","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute  4123 Allschwil Switzerland"},{"name":"University of Basel  4003 Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Merz","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences Albert-Ludwigs-Universit\u00e4t Freiburg  Albertstr. 25 79104 Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Ramos\u2010Morales","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg CNRS INSERM Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire  UMR 7104, U 1258 67400 Illkirch France"},{"name":"Department of Integrated Structural Biology IGBMC  1 rue Laurent Fries, B.P. 10142 67404 Illkirch Cedex France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvin D.","family":"de Araujo","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences University of Toronto Mississauga  3359 Mississauga Road North Mississauga ON L5L 1C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Romier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg CNRS INSERM Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire  UMR 7104, U 1258 67400 Illkirch France"},{"name":"Department of Integrated Structural Biology IGBMC  1 rue Laurent Fries, B.P. 10142 67404 Illkirch Cedex France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences Albert-Ludwigs-Universit\u00e4t Freiburg  Albertstr. 25 79104 Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Keiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute  4123 Allschwil Switzerland"},{"name":"University of Basel  4003 Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick T.","family":"Gunning","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences University of Toronto Mississauga  3359 Mississauga Road North Mississauga ON L5L 1C6 Canada"},{"name":"Department of Chemistry University of Toronto  80 St. George Street Toronto ON M5S 3H6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"World Health Organization \u201cSchistosomiasis \u201d can be found underhttps:\/\/www.who.int\/news-room\/fact-sheets\/detail\/schistosomiasis 2022."},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.15.25"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61949-2"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.9b00354"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40249-016-0215-9"},{"journal-title":"ACS Infect. 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