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

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.

• Authors: Zhu-Ping Xiao, Zhi-Yun Peng, Jing-Jun Dong, Rui-Cheng Deng, Xu-Dong Wang, Hui Ouyang, Pan Yang, Juan He, Yuan-Feng Wang, Man Zhu, Xiao-Chun Peng, Wan-Xi Peng, Hai-Liang Zhu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 68 Pg. 212-21 (Oct 2013) ISSN: 1768-3254 [Electronic] France
• PMID: 23974021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Hydroxamic Acids
• Urease

Topics

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