Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design

J Med Chem. 2024 May 9;67(9):7158-7175. doi: 10.1021/acs.jmedchem.4c00021. Epub 2024 Apr 23.


Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pentosyltransferases* / antagonists & inhibitors
  • Pentosyltransferases* / metabolism
  • Structure-Activity Relationship
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei brucei / enzymology


  • hypoxanthine-guanine-xanthine phosphoribosyltransferase
  • Pentosyltransferases
  • Enzyme Inhibitors