期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 32, 期 1, 页码 821-831出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2017.1326915
关键词
Isoxazol-5(2H)-one; human neutrophil elastase; HNE inhibitor; chemical stability; molecular docking
资金
- National Institutes of Health IDeA Program COBRE [GM110732]
- USDA National Institute of Food and Agriculture Hatch [1009546]
- Ministry of Education and Science of the Russian Federation [4.8192.2017]
- University of Montana System Research Initiative [51040-MUSRI2015-03]
- Montana State University Agricultural Experiment Station
Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure- activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value = 20 nM) and chemical stability in aqueous buffer (t(1/2) = 8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups. [GRAPHICS]
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据