Design of Helicobacter pylori glutamate racemase inhibitors as selective antibacterial agents: a novel pro-drug approach to increase exposure

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4716-22. doi: 10.1016/j.bmcl.2008.06.092. Epub 2008 Jul 2.


High-throughput screening uncovered a pyrazolopyrimidinedione hit as a selective, low micromolar inhibitor of Helicobacter pylori glutamate racemase (MurI). Variation of the substituents around the scaffold led to low nanomolar inhibitors and improved antibacterial activity. The challenge in this program was to translate excellent enzyme inhibition into potent antibacterial activity and pharmacokinetics suitable for oral therapy. Compounds were profiled for MurI inhibition, activity against H. pylori, microsomal stability, and pharmacokinetics in mice. Iterative cycles of analog synthesis and biological testing led to compounds with substituents optimized for both low MICs (2 microg/ml) and good microsomal stability. In order to achieve high bioavailability, a novel pro-drug approach was implemented wherein a solubilizing sulfoxide moiety is oxidized in vivo to a sulfone.

MeSH terms

  • Amino Acid Isomerases / antagonists & inhibitors
  • Amino Acid Isomerases / chemistry*
  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Biological Availability
  • Drug Design
  • Helicobacter Infections / drug therapy*
  • Helicobacter pylori / enzymology*
  • Inhibitory Concentration 50
  • Mice
  • Microbial Sensitivity Tests
  • Models, Chemical
  • Prodrugs
  • Protein Binding
  • Sulfoxides / chemistry
  • Time Factors


  • Anti-Bacterial Agents
  • Prodrugs
  • Sulfoxides
  • Amino Acid Isomerases
  • glutamate racemase