A high-throughput screen of the GlaxoSmithKline kinase-focused screening collection was performed against Trypanosoma brucei, the parasite responsible for a neglected tropical disease known as human African trypanosomiasis. As a result, 797 compounds were grouped into 59 clusters of structurally similar compounds that are potent inhibitors of T. brucei proliferation. In another study, NVP-BEZ235, a known human kinase inhibitor and phase III clinical candidate for cancer treatment, had been reported as a subnanomolar growth inhibitor of T. brucei. By using information from the GSK screen and NVP-BEZ235, we are proposing and synthesizing new structures that are specific for T. brucei. Our hit-to-lead medicinal chemistry effort is focused on identifying structures that improve their potency as T. brucei inhibitors while also maintaining good absorption, distribution, metabolism, and excretion (ADME) properties, particularly aqueous solubility. We have been investigating analogs around this series, making modifications in both the head and tail groups, and this will be discussed.

Synthesis of derivations from repurposed drug leads to find a new treatment for human African trypanosomiasis

256th National Meeting (2018)

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