Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and it is life threatening if left untreated. Current drugs for this disease are poor, with high toxicity and inconvenient dosing regimens. In the interest of identification of new kinase-targeting chemotypes against T. brucei, we have performed HTS screening of 42,444 focused inhibitors and identified 797 potent inhibitors of parasite growth with greater than 100-fold selectivity over human HepG2 cells. From this set of hits, a cluster of diaminopurine derived compounds was identified. In the present work, we have designed and synthesized several analogs around one of the HTS hits N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (NEU-0001106). Work involving exploration of structure activity relationships, structure property relationships, and identification of a potent lead compound with improved ADME properties will be reported, as well as progress towards establishing proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.

Diaminopurines: Structure activity relationships and structure property relationships towards a lead for human African trypanosomiasis inhibitors

256th National Meeting (2018)

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