Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis

Matthew W. Nowicki, Lindsay B. Tulloch, Liam Worralll, Iain W. McNae, Veronique Hannaert, Paul A. M. Michels, Linda A. Fothergill-Gilmore, Malcolm D. Walkinshaw, Nicholas J. Turner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of Trypanosoma and Leishmania. We report the design and the synthesis of inhibitors targeted against Trypanosoma brucei phosphofructokinase (PFK) and Leishmania mexicana pyruvate kinase (PyK). Stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with IC(50) values of 23 mu M and 26 mu M against PFK and PyK, respectively. Trypanocidal activity also showed potency in the low micromolar range and confirms these inhibitors as promising candidates for the development towards the design of anti-trypanosomal drugs. (c) 2008 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)5050-5061
Number of pages12
JournalBioorganic & Medicinal Chemistry
Volume16
Issue number9
DOIs
Publication statusPublished - 1 May 2008

Keywords

  • Trypanosome
  • REAGENTS
  • pyruvate kinase
  • glycolysis
  • drug development
  • PURIFICATION
  • PRODUCTS
  • inhibitors
  • phosphofructokinase
  • PYRUVATE-KINASE
  • CRYSTAL-STRUCTURE
  • PHOSPHOFRUCTOKINASE
  • Leishmania
  • DERIVATIVES
  • parasite
  • EVOLUTION
  • TRYPANOSOMA-BRUCEI

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