Human African trypanosomiasis (HAT), also known as sleeping sickness, is one of 20 neglected tropical diseases, as classified by the World Health Organization. The disease affects a reported ~2000 people annually primarily in sub-Saharan Africa, with millions more living in endemic areas. HAT is caused by infection with the protozoan parasite Trypanosoma brucei of which there are two subspecies that cause human infection and, if left untreated, is ultimately fatal. To identify new chemotypes, a high-throughput screen of 42,444 kinase-targeted inhibitors from the GSK collection was performed against T. brucei. As a result, 797 sub-micromolar inhibitors of T. brucei growth were identified and were categorized into 59 clusters, based on common substructures. A series of substituted azaindoles were selected for medicinal chemistry optimization due to their potent activity against T. brucei and their overall good absorption, distribution, metabolism and excretion (ADME) profile. The structure-activity (SAR) and structure-property relationships (SPR) of this cluster will be discussed.

SAR exploration of a novel series of compounds for human African trypanosomiasis

256th National Meeting (2018)

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