The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections

Wei-Wei Ni; Qi Liu; Shen-Zhen Ren; Wei-Yi Li; Li-Li Yi; Heng Jing; Li-Xin Sheng; Qin Wan; Ping-Fu Zhong; Hai-Lian Fang; Hui Ouyang; Zhu-Ping Xiao; Hai-Liang Zhu

doi:10.1016/j.bmc.2018.07.003

The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections

Bioorg Med Chem. 2018 Aug 7;26(14):4145-4152. doi: 10.1016/j.bmc.2018.07.003. Epub 2018 Jul 4.

Authors

Wei-Wei Ni¹, Qi Liu¹, Shen-Zhen Ren², Wei-Yi Li¹, Li-Li Yi¹, Heng Jing¹, Li-Xin Sheng¹, Qin Wan¹, Ping-Fu Zhong¹, Hai-Lian Fang¹, Hui Ouyang¹, Zhu-Ping Xiao³, Hai-Liang Zhu⁴

Affiliations

¹ National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
³ National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xiaozhuping2005@163.com.
⁴ National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: zhuhl@nju.edu.cn.

PMID: 29983280
DOI: 10.1016/j.bmc.2018.07.003

Abstract

Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC₅₀ = 0.061 ± 0.003 μM) and intact cell (IC₅₀ = 0.89 ± 0.05 μM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.

Keywords: Helicobacter pylori; Kinetics; Phenoxyacylhydroxamic acid; Urease inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Helicobacter Infections / drug therapy*
Helicobacter Infections / metabolism
Helicobacter pylori / cytology
Helicobacter pylori / drug effects*
Helicobacter pylori / enzymology
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Kinetics
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Urease / antagonists & inhibitors*
Urease / isolation & purification
Urease / metabolism

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Hydroxamic Acids
Urease