Synthesis, molecular docking and kinetic properties of β-hydroxy-β-phenylpropionyl-hydroxamic acids as Helicobacter pylori urease inhibitors

Eur J Med Chem. 2013 Oct:68:212-21. doi: 10.1016/j.ejmech.2013.07.047. Epub 2013 Aug 9.

Abstract

Inhibition of urease results in Helicobacter pylori growth arrest in the stomach, promoting urease as promising targets for gastrointestinal ulcer therapy. Twenty hybrid derivatives of flavonoid scaffold and hydroxamic acid, β-hydroxy-β-phenylpropionylhydroxamic acids, were therefore synthesized and evaluated against H. pylori urease. Biological evaluation of these compounds showed improved urease inhibition exhibiting micromolar to mid-nanomolar IC50 values. Most importantly, 3-(3-chlorophenyl)-3-hydroxypropionyl-hydroxamic acid (6g) exhibited high potency with IC50 of 0.083±0.004 μM and Ki of 0.014±0.003 μM, indicating that 6g is an excellent candidate to develop novel antiulcer agent. A mixture of competitive and uncompetitive mechanism was putatively proposed to understand the inconsistency between the crystallographic and kinetic studies for the first time, which is supported by our molecular docking studies.

Keywords: A mixture of competitive and uncompetitive mechanism; Helicobacter pylori urease; Hydroxamic acid; Inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Helicobacter pylori / drug effects*
  • Helicobacter pylori / enzymology*
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / metabolism
  • Hydroxamic Acids / pharmacology*
  • Inhibitory Concentration 50
  • Kinetics
  • Molecular Docking Simulation*
  • Molecular Structure
  • Urease / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Urease