Simple phosphonic inhibitors of human neutrophil elastase

Sieńczyk, Marcin; Winiarski, Łukasz; Kasperkiewicz, Paulina; Psurski, Mateusz; Wietrzyk, Joanna; Oleksyszyn, Józef

doi:10.1016/j.bmcl.2011.01.083

Cited by 19 publications

(21 citation statements)

References 18 publications

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“…Our investigation of the influence of structurally diverse substitutions on the phenyl ester rings indicated that inclusion of electron‐withdrawing moieties increases the level of inhibition of SplA, as was previously reported for other proteases …”

Section: Discussionsupporting

confidence: 77%

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Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus

et al. 2013

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Staphylococcus aureus is responsible for a variety of human infections, including lifethreatening, systemic conditions. Secreted proteome, including a range of proteases, constitutes the major virulence factor of the bacterium. However, the functions of individual enzymes, in particular SplA protease, remain poorly characterized. Here, we report development of specific inhibitors of SplA protease. The design, synthesis, and activity of a series of a-aminoalkylphosphonate diaryl esters and their peptidyl derivatives are described. Potent inhibitors of SplA are reported, which may facilitate future investigation of physiological function of the protease. The binding modes of the high-affinity compounds Cbz-Phe P -(OC 6 H 4 24-SO 2 CH 3 ) 2 and Suc-Val-Pro-Phe P -(OC 6 H 5 ) 2 are revealed by high-resolution crystal structures of complexes with the protease. Surprisingly, the binding mode of both compounds deviates from previously characterized canonical interaction of a-aminoalkylphosphonate peptidyl derivatives and family S1 serine proteases.

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Section: Discussionsupporting

confidence: 77%

“…All final compounds were purified using column chromatography on silica gel. Other examined phosphonate inhibitors were synthesized as described previously: 1 , 2–4 , 5–6 , 7 , 8–9 , 10–16 , 17–18 , 20–22 , 29–34 , and 41 …”

Section: Methodsmentioning

confidence: 99%

Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus

et al. 2013

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“…On the other hand, the inactivity of compounds 2a – f , 5a , b , and 6a , b , bearing a different carbonyl group (i.e., amide or ester) at N-1, suggests that the thiazol-2-(3 H )-one nucleus itself is not a suitable scaffold for HNE inhibitors. The lack of activity for compounds 8 – 10 is a further support for this conclusion, considering the presence of a bulky phosphonic fragment, which is a typical residue in potent HNE inhibitors reported in the literature [26]. …”

Section: Resultsmentioning

confidence: 61%

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

Crocetti

Bartolucci

Cilibrizzi

et al. 2017

Chemistry Central Journal

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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. Electronic supplementary materialThe online version of this article (10.1186/s13065-017-0358-1) contains supplementary material, which is available to authorized users.

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“…The obtained phosphites were reacted with benzaldehyde and benzyl carbamate, according to literature [18–20], providing the desired diaryl (benzyloxycarbonylamino)(phenyl)methylphosphonates (Scheme 1) with good yields (59–86%). Unfortunately, the reaction of phosphite obtained from 7-hydroxycoumarine failed, since it appeared to be unstable upon harsh reaction conditions and underwent decomposition as seen by 31 P NMR.…”

Section: Resultsmentioning

confidence: 99%