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The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62\u2009000 compound library against<\/jats:italic> T.\u2005brucei <jats:italic>TryR. Further work was undertaken to optimise potency and selectivity of two novel\u2010compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. 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