3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation

• Published in: Bioorganic & medicinal chemistry 2016-10, Vol.24 (19), p.4519-4527
• Main Authors: Shi, Wei-Kang, Deng, Rui-Cheng, Wang, Peng-Fei, Yue, Qin-Qin, Liu, Qi, Ding, Kun-Ling, Yang, Mei-Hui, Zhang, Hong-Yu, Gong, Si-Hua, Deng, Min, Liu, Wen-Run, Feng, Qiu-Ju, Xiao, Zhu-Ping, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: 3-Arylpropionylhydroxamic acid; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Blood Proteins - metabolism; H. pylori urease inhibitor; Helicobacter Infections - drug therapy; Helicobacter Infections - microbiology; Helicobacter pylori - drug effects; Helicobacter pylori - enzymology; Humans; Hydroxamic Acids - chemistry; Hydroxamic Acids - metabolism; Hydroxamic Acids - pharmacology; Kinetics; Kinetics study; Molecular Docking Simulation; Non-linear fitting; Plasma protein binding; Rabbits; Structure-Activity Relationship; Urease - antagonists & inhibitors; Urease - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.07.052

[Display omitted] •3-Arylpropionylhydroxamic acid derivatives showed a mixed inhibition mechanism.•Mixed urease inhibitors with enhanced inhibitory activities have been synthesized.•Urea showed substrate inhibition against H. pylori urease. Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori-caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5-chlorophenyl)-3-hydroxypropionylhydroxamic acid (d24) was the most active inhibitor with IC50 of 0.15±0.05μM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12μg·mL−1 for Ki and Ki′, respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins.