{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:20:05Z","timestamp":1788265205469,"version":"build-2803163510"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>There is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852,<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adult<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Schistosoma mansoni<\/jats:named-content>worms<jats:italic>in vitro<\/jats:italic>. Active compounds were evaluated with a cytotoxicity assay,<jats:italic>in silico<\/jats:italic>calculations, metabolic stability studies, and an<jats:italic>in vivo<\/jats:italic>assay with mice harboring adult<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. mansoni<\/jats:named-content>worms. Of the 46 compounds tested at 33.3 \u03bcM, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC<jats:sub>90<\/jats:sub>s) of \u226410 \u03bcM against adult worms, with selectivity indexes of \u22652.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactory<jats:italic>in vitro<\/jats:italic>results and<jats:italic>in silico<\/jats:italic>predictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg\/kg of body weight to<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. mansoni<\/jats:named-content>-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of the<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032-diarylurea MMV665852 had high efficacy against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. mansoni<\/jats:named-content><jats:italic>in vitro<\/jats:italic>and favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.<\/jats:p>","DOI":"10.1128\/aac.04463-14","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T16:36:49Z","timestamp":1426091809000},"page":"1935-1941","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":33,"title":["Activities of<i>N<\/i>,<i>N<\/i>\u2032-Diarylurea MMV665852 Analogs against Schistosoma mansoni"],"prefix":"10.1128","volume":"59","author":[{"given":"Noemi","family":"Cowan","sequence":"first","affiliation":[{"name":"Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland"},{"name":"University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"D\u00e4twyler","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pharmacy, University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Ernst","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pharmacy, University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunkai","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Vennerstrom","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Spangenberg","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture (MMV), Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Keiser","sequence":"additional","affiliation":[{"name":"Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland"},{"name":"University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61949-2"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2013.844066"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2007.05.031"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-012-3151-z"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt491"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0062906"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002610"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.07.034"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml100083c"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050716a"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2004.06.097"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2011.10.126"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(00)00129-0"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.21068"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.10.056"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2013.01.023"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.06.034"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01537-06"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182009990965"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06177-11"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200390016"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-005-8694-y"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm970530e"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.10"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02741-14"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.12.1.147"},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0090-9556(25)06322-6","article-title":"Biotransformation products of 3,4,4\u2032-trichlorocarbanilide in rat, monkey, and man","volume":"6","author":"Birch CG","year":"1978","unstructured":"Birch CG, Hiles RA, Eichhold TH, Jeffcoat AR, Handy RW, Hill JM, Willis SL, Hess TR, Wall ME. 1978. 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