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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.
Highlights
Human neutrophil elastase (HNE) is a small, soluble glycoprotein of about 30 kDa belonging to the chymotrypsin family of serine proteases [1] and is expressed primarily in neutrophils, and in monocytes and mast cells [2]
HNE performs its proteolytic action through a catalytic triad consisting of Ser195Asp102-His57, where the powerful nucleophile oxygen of Ser195 attacks the carbonyl carbon involved in the peptide bond [4, 5]
HNE is involved in a variety of pathologies affecting the respiratory system, such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI)
Summary
Human neutrophil elastase (HNE) is a small, soluble glycoprotein of about 30 kDa belonging to the chymotrypsin family of serine proteases [1] and is expressed primarily in neutrophils, and in monocytes and mast cells [2]. Our research group is involved in the design and synthesis of small molecules with HNE inhibitory activity, and we have identified a number of new classes of inhibitors based on different bicyclic scaffolds [14–17]. We recently reported new isoxazolone-based derivatives with HNE inhibitory activity in the low nanomolar range (IC50 = 20–96 nM) [18]. HNE catalytic residue) and define the endocyclic carbonyl at position 5 of the isoxazolone core as a critical requirement for inhibitory activity [18]. Starting from these results, we report here the development and analytical characterization of a new series of heterocyclic compounds based on the thiazol-2-(3H)-one scaffold originally designed as possible HNE inhibitors (Fig. 2). The first pathway involves carbonyl sulfide loss, which is favored in heterocyclic moieties, followed by a rearrangement and
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