title: 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: College of Chemistry and Chemical Engineering, Key Laboratory of Hunan Forest Products and Chemical Industry Engineering, Jishou University, Jishou 416000, PR China. Electronic address: xiaozhuping2005@163.com.
authors: Zhu-Ping
authors: ZP
authors: Xiao
authors: Zhi-Yun
authors: ZY
authors: Peng
authors: Jing-Jun
authors: JJ
authors: Dong
authors: Rui-Cheng
authors: RC
authors: Deng
authors: Xu-Dong
authors: XD
authors: Wang
authors: Hui
authors: H
authors: Ouyang
authors: Pan
authors: P
authors: Yang
authors: Juan
authors: J
authors: He
authors: Yuan-Feng
authors: YF
authors: Wang
authors: Man
authors: M
authors: Zhu
authors: Xiao-Chun
authors: XC
authors: Peng
authors: Wan-Xi
authors: WX
authors: Peng
authors: Hai-Liang
authors: HL
authors: Zhu
mesh_terms: D001667:Binding, Competitive; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D014510:Urease / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D014510:Urease
keywords: A mixture of competitive and uncompetitive mechanism; Helicobacter pylori urease; Hydroxamic acid; Inhibitor