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

Oleg A. Volkov, Anthony J. Brockway, Stephen A. Wring, Michael Peel, Zhe Chen, Margaret A. Phillips, Jef K. De Brabander

Research output: Contribution to journalArticle

5 Scopus citations

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 series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.

Original languageEnglish (US)
Pages (from-to)1182-1203
Number of pages22
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
DOIs
StatePublished - Feb 8 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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