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In this study, initial screening revealed the triazole\u2010based hydroxamate <jats:bold>2\u2009b<\/jats:bold> (<jats:italic>N<\/jats:italic>\u2010hydroxy\u20101\u2010phenyl\u20101<jats:italic>H<\/jats:italic>\u20101,2,3\u2010triazole\u20104\u2010carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target <jats:italic>Schistosoma mansoni<\/jats:italic> histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the <jats:bold>2\u2009b<\/jats:bold>\/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of <jats:bold>2\u2009b<\/jats:bold> led to the discovery of 4\u2010fluorophenoxy derivative <jats:bold>21<\/jats:bold> (1\u2010[5\u2010chloro\u20102\u2010(4\u2010fluorophenoxy)phenyl]\u2010<jats:italic>N<\/jats:italic>\u2010hydroxy\u20101<jats:italic>H<\/jats:italic>\u20101,2,3\u2010triazole\u20104\u2010carboxamide), a nanomolar smHDAC8 inhibitor (IC<jats:sub>50<\/jats:sub>=0.5\u2005\u03bcM), exceeding the smHDAC8 inhibitory activity of <jats:bold>2\u2009b<\/jats:bold> and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole\u2010based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.<\/jats:p>","DOI":"10.1002\/cmdc.201900583","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T10:34:47Z","timestamp":1575887687000},"page":"571-584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Structure\u2010Based Design, Synthesis, and Biological Evaluation of Triazole\u2010Based smHDAC8 Inhibitors"],"prefix":"10.1002","volume":"15","author":[{"given":"Dmitrii V.","family":"Kalinin","sequence":"first","affiliation":[{"name":"Department of Chemistry Institute of Organic Chemistry University of Hamburg  Martin-Luther-King-Platz\u20056 20146 Hamburg Germany"},{"name":"German Center for Infection Research (DZIF) partner site Hamburg-L\u00fcbeck-Borstel-Riems"},{"name":"Institute of Pharmaceutical and Medicinal Chemistry University of M\u00fcnster  Corrensstr. 48 48149 M\u00fcnster Germany"},{"name":"Cells-in-Motion Cluster of Excellence (EXC 1003 - 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