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Title

Novel 1,2-dihydroquinazolin-2-ones: Design, synthesis, and biological evaluation against Trypanosoma brucei

AuthorsPham, ThanhTruc; Walden, Madeline; Butler, Christopher; Díaz-González, Rosario; Pérez-Moreno, Guiomar; Ceballos-Pérez, Gloria; Gómez-Pérez, Veronica; García-Hernández, Raquel; Zecca, Henry; Krakoff, Emma; Kopec, Brian; Ichire, Ogar; Mackenzie, Caden; Pitot, Marika; Ruiz-Pérez, Luis Miguel; Gamarro, Francisco; González-Pacanowska, D.; Navarro, M.; Dounay, Amy B.
KeywordsTrypanosomiasis
HAT
Trypanosoma brucei
Quinazolinone
Hit-to-lead
Issue Date15-Aug-2017
PublisherElsevier
CitationBioorganic and Medicinal Chemistry Letters
AbstractIn 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery.
Publisher version (URL)https://www.ncbi.nlm.nih.gov/pubmed/28729055
URIhttp://hdl.handle.net/10261/178573
DOI10.1016/j.bmcl.2017.07.032
ISSN0960-894X
E-ISSN1464-3405
Appears in Collections:(IPBLN) Artículos

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