Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase.

ABSTRACT: New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the se

SUBMITTER: Volkov OA 

PROVIDER: S-EPMC5965259 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature