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With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK\u2010256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure\u2013activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of <jats:italic>T.\u00a0brucei<\/jats:italic> cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported <jats:italic>apo<\/jats:italic> structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.<\/jats:p>","DOI":"10.1111\/cbdd.12443","type":"journal-article","created":{"date-parts":[[2014,10,4]],"date-time":"2014-10-04T05:11:23Z","timestamp":1412399483000},"page":"549-564","source":"Crossref","is-referenced-by-count":14,"title":["Repurposing Human <scp>PDE<\/scp>4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human <scp>PDE<\/scp>4 Inhibitor <scp>GSK<\/scp>\u2010256066 as Inhibitors of <scp>PDEB<\/scp>1 of <i>Trypanosoma brucei<\/i>"],"prefix":"10.1111","volume":"85","author":[{"given":"Stefan O.","family":"Ochiana","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology Northeastern University 417 Egan Research Center, 360 Huntington Avenue Boston MA 02115 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas D.","family":"Bland","sequence":"additional","affiliation":[{"name":"Marine Biological Laboratory Josephine Bay Paul Center for Comparative Molecular Biology and Evolution 7 MBL Street Woods Hole MA 02543 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Settimo","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology Northeastern University 417 Egan Research Center, 360 Huntington Avenue Boston MA 02115 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert K.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Marine Biological Laboratory Josephine Bay Paul Center for Comparative Molecular Biology and Evolution 7 MBL Street Woods Hole MA 02543 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P.","family":"Pollastri","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology Northeastern University 417 Egan Research Center, 360 Huntington Avenue Boston MA 02115 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,11,18]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"SavioliL. 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