Trypanosoma brucei is the protozoan parasite that causes human African trypanosomiasis (HAT). HAT is a neglected tropical disease (NTD) that burdens millions of people in poor, rural communities of sub-Saharan Africa. In collaboration with the Tres Cantos OpenLab Foundation at GlaxoSmithKline, a high-throughput screen was performed using a library of 42,444 known human kinase inhibitors against T. brucei. Potent compounds were further screened in dose response and selectivity assays to narrow down the pool of potential hits. The remaining 797 compounds were analyzed for structural similarity and sorted into clusters. A series of 2,4-substituted azaindoles was chosen to advance into hit-to-lead optimization due to its high potency, fast-acting and cidal nature, and good in vitro pharmacokinetic properties. The lead hit from this cluster, NEU-1200, is highly cleared and does not show efficacy in vivo. Analogs of NEU-1200 have been synthesized and an understanding of the structure-activity and structure-property relationships has been established. Furthermore, using a parasite hopping approach we have found these compounds to be active against blood and liver stage Plasmodium falciparum infections. The improvements in metabolism and potency will be discussed, alongside the preliminary P. falciparum data.

Discovery of 2,4-substituted azaindoles as multi-parasite inhibitors: Utilizing a parasite-hopping approach to drug-discovery

256th National Meeting (2018)

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