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, Véronique Hannaert, Paul A. M. Michels, Linda A. Fothergill-Gilmore, Malcolm D. Walkinshaw, Nicholas J. Turner (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

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 23microM and 26microM 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.

Original languageEnglish
Pages (from-to)5050-5061
Number of pages12
JournalBioorganic & Medicinal Chemistry
Volume16
Issue number9
Early online date21 Mar 2008
DOIs
Publication statusPublished - 1 May 2008

Keywords

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors/chemical synthesis
  • Glycolysis
  • Inhibitory Concentration 50
  • Lead/chemistry
  • Leishmania mexicana/drug effects
  • Models, Molecular
  • Molecular Structure
  • Organometallic Compounds/chemical synthesis
  • Parasitic Sensitivity Tests
  • Phosphofructokinases/antagonists & inhibitors
  • Pyruvate Kinase/antagonists & inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship
  • Trypanocidal Agents/chemical synthesis
  • Trypanosoma brucei brucei/drug effects
  • Pyruvate kinase
  • Phosphofructokinase
  • Inhibitors
  • Leishmania
  • Trypanosome
  • Parasite
  • Drug development

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