3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation. Issue 19 (1st October 2016)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 19(2016)
• Page Start: 4519
• Page End: 4527
• Publication Date: 2016-10-01
• Subjects: 3-Arylpropionylhydroxamic acid -- H. pylori urease inhibitor -- Plasma protein binding -- Kinetics study -- Non-linear fitting; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.07.052
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 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. Abstract: 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 ± 0.05 μM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12 μg·mL −1 for K i and K i ′, respectively. The plasma protein binding assays suggested thatd24 exhibited moderate binding to human and rabbit plasma proteins.