Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

Abstract

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.

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Citation

Crocetti, Letizia, Gianluca Bartolucci, Agostino Cilibrizzi, Maria Paola Giovannoni, Gabriella Guerrini, Antonella Iacovone, Marta Menicatti, Igor A Schepetkin, Andrei I Khlebnikov, Mark T Quinn, and Claudia Vergelli. "Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors." Chemistry Central Journal 11, no. 1 (January 2018): 1-15. DOI: 10.1186/s13065-017-0358-1.
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