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

Bioorg Med Chem. 2008 May 1;16(9):5050-61. doi: 10.1016/j.bmc.2008.03.045. Epub 2008 Mar 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Enzyme Inhibitors
  • Organometallic Compounds
  • Trypanocidal Agents
  • Lead
  • Phosphofructokinases
  • Pyruvate Kinase