{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:45:22Z","timestamp":1790736322119,"version":"4.1.0"},"reference-count":19,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,9,23]],"date-time":"2015-09-23T00:00:00Z","timestamp":1442966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust","award":["077705"],"award-info":[{"award-number":["077705"]}]},{"name":"Wellcome Trust","award":["094090"],"award-info":[{"award-number":["094090"]}]},{"name":"Wellcome Trust","award":["WT083481"],"award-info":[{"award-number":["WT083481"]}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The enzyme <jats:italic>N<\/jats:italic>\u2010myristoyltransferase (NMT) from <jats:italic>Trypanosoma brucei<\/jats:italic> has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high\u2010throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X\u2010ray crystal structure of the thiazolidinone hit in <jats:italic>Leishmania major<\/jats:italic> NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X\u2010ray crystallography\/structure\u2010based design approach, the benzomorpholinone series was further optimised, increasing activity against <jats:italic>T.\u2005brucei<\/jats:italic> NMT by &gt;1000\u2010fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against <jats:italic>T.\u2005brucei<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/cmdc.201500301","type":"journal-article","created":{"date-parts":[[2015,9,23]],"date-time":"2015-09-23T09:41:20Z","timestamp":1443001280000},"page":"1821-1836","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Development of Small\u2010Molecule <i>Trypanosoma brucei N<\/i>\u2010Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode"],"prefix":"10.1002","volume":"10","author":[{"given":"Daniel","family":"Spinks","sequence":"first","affiliation":[{"name":"Drug Discovery Unit College of Life Sciences University of Dundee  Sir James Black Centre Dundee DD1 5EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Smith","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit 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