Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
| Autor: | Justin A. MacDonald, Eleonora Gianquinto, Marta Giorgis, Valentina Boscaro, Francesca Spyrakis, Federica Blua, Christina F. Sandall, Margherita Gallicchio, Elisabetta Marini, Massimo Bertinaria, Simone Gastaldi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Inflammasomes THP-1 Cells Stereochemistry interleukin-1β Interleukin-1beta ATP hydrolysis Interleukin-1β MD simulations NLRP3 inhibitors Pyroptosis Humans Macrophages NLR Family Pyrin Domain-Containing 3 Protein Imidazoles Pharmaceutical Science Organic chemistry NLR Family Analytical Chemistry law.invention 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine QD241-441 law Drug Discovery medicine Imidazole Physical and Theoretical Chemistry Binding site Acrylic acid integumentary system Chemistry pyroptosis Inflammasome Pyrin Domain-Containing 3 Protein In vitro 3. Good health 030104 developmental biology Chemistry (miscellaneous) 030220 oncology & carcinogenesis Recombinant DNA Molecular Medicine medicine.drug |
| Zdroj: | Molecules Volume 26 Issue 13 Molecules, Vol 26, Iss 3975, p 3975 (2021) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules26133975 |
| Popis: | In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. |
| Databáze: | OpenAIRE |
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