'Click chemistry' synthesis of a library of 1,2,3-triazole-substituted galactose derivatives and their evaluation against Trypanosoma cruzi and its cell surface trans-sialidase

Bioorg Med Chem. 2010 Apr 1;18(7):2412-27. doi: 10.1016/j.bmc.2010.02.053. Epub 2010 Mar 2.


Trypanosoma cruzi trans-sialidase (TcTS) plays a key role in the recognition and invasion of host cells and in enabling the parasite to escape the human immune response. To explore this potential drug target, we have synthesized a small library of substrate analogues based on 1,4-disubstituted 1,2,3-triazole derivatives of galactose modified at either the C-1 or C-6 positions. This was achieved by coupling the appropriate azido-sugars with a panel of 23 structurally diverse terminal alkynes by using the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction, giving a library of 46 derivatives in good to excellent yield and with complete regioselectivity. The sugar triazoles showed weak inhibition towards TcTS-catalyzed hydrolysis of 2'-(4-methylumbelliferyl)-alpha-d-N-acetylneuraminic acid in vitro (<40% inhibition at 1mM concentration); many of the compounds assessed proved to be acceptor substrates for the enzyme. Despite this modest inhibitory activity, in vitro trypanocidal activity assays against the trypomastigote form of T. cruzi Y strain revealed several compounds active in the low 100s of muM range. Further assessment of these compounds against cultured mouse spleen cells suggests a specific mode of anti-parasite action rather than a generic cytotoxic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azides / chemical synthesis
  • Cell Line
  • Cell Survival / drug effects
  • Chromatography, Thin Layer
  • Fluorometry
  • Galactose / analogs & derivatives*
  • Galactose / chemical synthesis*
  • Galactose / pharmacology
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • N-Acetylneuraminic Acid / chemistry
  • N-Acetylneuraminic Acid / metabolism
  • Neuraminidase / antagonists & inhibitors*
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrophotometry, Ultraviolet
  • Spleen / cytology
  • Spleen / drug effects
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology*
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / enzymology*


  • Azides
  • Indicators and Reagents
  • Membrane Proteins
  • Triazoles
  • Trypanocidal Agents
  • Neuraminidase
  • N-Acetylneuraminic Acid
  • Galactose