TY - JOUR
T1 - Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors
AU - Crocetti, Letizia
AU - Bartolucci, Gianluca
AU - Cilibrizzi, Agostino
AU - Giovannoni, Maria Paola
AU - Guerrini, Gabriella
AU - Iacovone, Antonella
AU - Menicatti, Marta
AU - Schepetkin, Igor A.
AU - Khlebnikov, Andrei I.
AU - Quinn, Mark T.
AU - Vergelli, Claudia
N1 - Funding Information:
This research was supported in part by National Institutes of Health IDeA Program COBRE Grant GM110732; USDA National Institute of Food and Agriculture Hatch Project 1009546; the Montana State University Agricultural Experiment Station; and Tomsk Polytechnic University Competitiveness Enhancement Program Grant, Project TPU CEP_IHTP_73\2017.
Funding Information:
National Institutes of Health IDeA Program COBRE Grant GM110732 USDA National Institute of Food and Agriculture Hatch Project 1009546 Tomsk Polytechnic University Competitiveness Enhancement Program Grant, Project TPU CEP_IHTP_73\2017.
Publisher Copyright:
© The Author(s) 2017.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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 µM), 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.
AB - 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 µM), 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.
KW - ERMS
KW - Human neutrophil elastase
KW - LC-MS/MS
KW - Synthesis
KW - Thiazol-2-(3H)-one
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U2 - 10.1186/s13065-017-0358-1
DO - 10.1186/s13065-017-0358-1
M3 - Article
AN - SCOPUS:85047203044
VL - 11
JO - Chemistry Central Journal
JF - Chemistry Central Journal
SN - 1752-153X
IS - 1
M1 - 127
ER -