A unified approach toward the rational design of selective low nanomolar human neutrophil elastase inhibitors

Areias, Laurinda R.P.; Ruivo, Eduardo; Gonçalves, Lídia; Duarte, M. Teresa; André, Vânia; Moreira, Rui; Lucas, Susana D.; Guedes, Rita C.

doi:10.1039/c5ra07783d

Cited by 4 publications

(1 citation statement)

References 16 publications

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“…A very interesting group of compounds that caught our attention are azetidine-2,4-diones, also known as 4-oxo-β-lactams [ 26 ]. These compounds showed the ability to serine acylation in HNE, and further research on the structure optimization showed that N -phenyl derivatives of 3,3-diethylazetidine-2,4-dione G ( Figure 1 ) show much higher activity and selectivity towards HNE [ 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity

Donarska

Świtalska

Wietrzyk

et al. 2022

IJMS

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A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a–3j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02–44.59 nM, with mixed mechanism of action. Additionally, the most active compounds 3c and 3e demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC50 values, suggesting that the inhibition properties are largely dependent on the stage of ligand alignment in the binding cavity. The inhibition properties are correlated with the energy level of substrates of the reaction of ligand with Ser195. Moreover, most compounds showed high and broad-spectrum antiproliferative activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast adenocarcinoma (MDA-MB-231), and urinary bladder carcinoma (UMUC-3), with IC50 values of 4.59–9.86 μM. Additionally, compounds 3c and 3e can induce cell cycle arrest at the G2/M phase and apoptosis via caspase-3 activation, leading to inhibition of A549 cell proliferation. These findings suggest that these new types of drugs could be used to treat cancer and other diseases in which immunoreactive HNE is produced.

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Section: Introductionmentioning

confidence: 99%

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity

Donarska

Świtalska

Wietrzyk

et al. 2022

IJMS

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Starch nanocapsules containing a novel neutrophil elastase inhibitor with improved pharmaceutical performance

Marto

Ruivo

Lucas

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications

Crocetti

Quinn

Schepetkin

et al. 2019

Expert Opinion on Therapeutic Patents

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A unified approach toward the rational design of selective low nanomolar human neutrophil elastase inhibitors

Abstract: A computer-aided campaign boosted the discovery of potent human neutrophil elastase (HNE) inhibitors.

Cited by 4 publications

References 16 publications

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity

Starch nanocapsules containing a novel neutrophil elastase inhibitor with improved pharmaceutical performance

A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications

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