期刊
CHEMISTRY CENTRAL JOURNAL
卷 11, 期 -, 页码 -出版社
SPRINGEROPEN
DOI: 10.1186/s13065-017-0358-1
关键词
Thiazol-2-(3H)-one; Synthesis; LC-MS/MS; ERMS; Human neutrophil elastase
资金
- National Institutes of Health IDeA Program COBRE [GM110732]
- USDA National Institute of Food and Agriculture Hatch [1009546]
- Tomsk Polytechnic University Competitiveness Enhancement Program Grant [TPU CEP_IHTP_73\2017]
Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family and is involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here the synthesis of new thiazol-2-(3H)-ones as an elaboration of potent HNE inhibitors with an isoxazol-5-(2H)-one scaffold that we recently identified. Two-dimensional NMR spectroscopic techniques and tandem mass spectrometry allowed us to correctly assign the structure of the final compounds arising from both tautomers of the thiazol-2-(3H)-one nucleus (N-3 of the thiazol-2-(3H)-one and 3-OH of the thiazole). All new compounds were tested as HNE inhibitors, and no activity was found at the highest concentration used (40 mu M), demonstrating that the thiazol-2-(3H)-one is not a good scaffold for HNE inhibitors. Molecular modelling experiments indicate that the low-energy pose might limit the nucleophilic attack on the endocyclic carbonyl group of the thiazolone-based compounds by HNE catalytic Ser195, in contrast to isoxazol-5-(2H)-one analogues.
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