Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Bioorg Med Chem. 2013 Sep 1;21(17):5629-46. doi: 10.1016/j.bmc.2013.02.016. Epub 2013 Mar 5.

Abstract

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

Keywords: HGXPRTase; Malaria; Phosphoribosyltransferase; Protozoa; Purine salvage.

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology
  • Aza Compounds / chemistry
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Kinetics
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry*
  • Nucleosides / pharmacology
  • Pentosyltransferases / antagonists & inhibitors*
  • Pentosyltransferases / metabolism
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protein Binding

Substances

  • Antimalarials
  • Aza Compounds
  • Enzyme Inhibitors
  • Nucleosides
  • Pentosyltransferases
  • hypoxanthine-guanine-xanthine phosphoribosyltransferase