Human African trypanosomiasis (HAT), one of 17 neglected tropical diseases (NTDs) designated by the World Health Organization, affects approximately 8,000 people in the remotest parts of Africa; the disease is devastating to those afflicted. HAT is caused by the protozoan parasite Trypanosoma brucei, and once the parasite crosses the blood brain barrier it causes disrupted sleep patterns, brain damage and eventual death. Current treatments for this disease are associated with complex treatment regimens and often result in the development of long term health issues; in addition, reports of resistance are becoming more frequent. Combined, these factors contribute to a need for new lead compounds to fill the drug discovery pipeline for HAT. To this end, we employed a lead repurposing strategy, whereby lead compounds against a human target are screened against the disease-causing parasite. We previously reported the results of a whole organism high-throughput screen of 42,444 inhibitors from the GSK kinase-focused screening collection that led to the identification of 797 sub-micromolar inhibitors of T. brucei growth; a number of the resulting clusters have been progressed to medicinal chemistry optimization. The structure-activity relationships (SAR), pharmacophore identification, and speed of action studies within one of these clusters with high potency, excellent selectivity and good absorption, distribution, metabolism, and excretion (ADME) properties will be discussed.

Hit-to-lead studies and pharmacophore identification within a novel class of anti-trypanosomal agents

254th National Meeting (2017)

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