Abstract
<jats:p> Despite recent advances in the development of therapeutics for human African trypanosomiasis, new treatments are needed to populate the drug pipeline in case of failure and resistance. A previously reported high throughput screen of human kinase inhibitors identified the pyrazolopyridine scaffold as an inhibitor of <jats:italic toggle="yes">Trypanosoma brucei</jats:italic> ( <jats:italic toggle="yes">T.b</jats:italic> .), which was subsequently optimized for antiparasitic activity. We report the structure-activity relationships (SAR) of the series, focused on improving antitrypanosomal activity and ADME properties, while using structure-based drug design (SBDD) to introduce parasite selectivity. Through these efforts, we identified analogs up to 11-fold more potent than the initial hits, and with up to 40-fold improvement in aqueous solubility. Selectivity for <jats:italic toggle="yes">T. brucei</jats:italic> over human kinases remains an area for improvement. </jats:p>