Discovery of Inhibitors of Trypanosoma brucei by Phenotypic Screening of a Focused Protein Kinase Library

• Published in: ChemMedChem Vol. 10; no. 11; pp. 1809 - 1820
• Main Authors: Woodland, Andrew, Thompson, Stephen, Cleghorn, Laura A. T., Norcross, Neil, De Rycker, Manu, Grimaldi, Raffaella, Hallyburton, Irene, Rao, Bhavya, Norval, Suzanne, Stojanovski, Laste, Brun, Reto, Kaiser, Marcel, Frearson, Julie A., Gray, David W., Wyatt, Paul G., Read, Kevin D., Gilbert, Ian H.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 01.11.2015; Wiley; Wiley Subscription Services, Inc
• Subjects: Cell Line; Chemistry, Medicinal; cidal; Dose-Response Relationship, Drug; Drug Discovery; Humans; kinases; Life Sciences & Biomedicine; Molecular Structure; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Phenotype; phenotypic; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Science & Technology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; static; Structure-Activity Relationship; Trypanosoma brucei; Trypanosoma brucei rhodesiense; Trypanosoma brucei rhodesiense - drug effects; Trypanosoma brucei rhodesiense - growth & development; TARGET; static; HUMAN AFRICAN TRYPANOSOMIASIS; DRUG DISCOVERY; MEDICINES; IDENTIFICATION; cidal; phenotypic; IN-VITRO; POTENT; kinases; ADMET RULES; Trypanosoma brucei; NEGLECTED DISEASE; LEISHMANIA

A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm. Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H‐imida...