The synthesis and kinetic evaluation of aryl α-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase

Eur J Med Chem. 2018 Oct 5:158:25-33. doi: 10.1016/j.ejmech.2018.08.089. Epub 2018 Aug 31.

Abstract

The trans-sialidase protein expressed by Trypanosoma cruzi is an important enzyme in the life cycle of this human pathogenic parasite and is considered a promising target for the development of new drug treatments against Chagas' disease. Here we describe α-amino phosphonates as a novel class of inhibitor of T. cruzi trans-sialidase. Molecular modelling studies were initially used to predict the active-site binding affinities for a series of amino phosphonates, which were subsequently synthesised and their IC50s determined in vitro. The measured inhibitory activities show some correlation with the predictions from molecular modelling, with 1-napthyl derivatives found to be the most potent inhibitors having IC50s in the low micromolar range. Interestingly, kinetic analysis of the mode of inhibition demonstrated that the α-aminophosphonates tested here operate in a non-competitive manner.

Keywords: Inhibitors; Non-competitive; Trans-sialidase; Trypanosoma cruzi; α-aminophosphonates.

MeSH terms

  • Amination
  • Chagas Disease / drug therapy*
  • Chagas Disease / parasitology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glycoproteins / antagonists & inhibitors*
  • Glycoproteins / chemistry
  • Glycoproteins / metabolism
  • Humans
  • Molecular Docking Simulation
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / chemistry
  • Neuraminidase / metabolism
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology*
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects
  • Trypanosoma cruzi / enzymology*

Substances

  • Enzyme Inhibitors
  • Glycoproteins
  • Organophosphonates
  • Trypanocidal Agents
  • trans-sialidase
  • Neuraminidase