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Article

Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

by
Simone Gastaldi
1,
Valentina Boscaro
1,
Eleonora Gianquinto
1,
Christina F. Sandall
2,
Marta Giorgis
1,
Elisabetta Marini
1,
Federica Blua
1,
Margherita Gallicchio
1,
Francesca Spyrakis
1,
Justin A. MacDonald
2 and
Massimo Bertinaria
1,*
1
Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Torino, Italy
2
Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(13), 3975; https://doi.org/10.3390/molecules26133975
Submission received: 14 June 2021 / Revised: 23 June 2021 / Accepted: 23 June 2021 / Published: 29 June 2021
(This article belongs to the Special Issue Inflammasome Inhibitors)
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Abstract

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.
Keywords: NLRP3 inhibitors; pyroptosis; interleukin-1β; ATP hydrolysis; MD simulations NLRP3 inhibitors; pyroptosis; interleukin-1β; ATP hydrolysis; MD simulations

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MDPI and ACS Style

Gastaldi, S.; Boscaro, V.; Gianquinto, E.; Sandall, C.F.; Giorgis, M.; Marini, E.; Blua, F.; Gallicchio, M.; Spyrakis, F.; MacDonald, J.A.; et al. Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor. Molecules 2021, 26, 3975. https://doi.org/10.3390/molecules26133975

AMA Style

Gastaldi S, Boscaro V, Gianquinto E, Sandall CF, Giorgis M, Marini E, Blua F, Gallicchio M, Spyrakis F, MacDonald JA, et al. Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor. Molecules. 2021; 26(13):3975. https://doi.org/10.3390/molecules26133975

Chicago/Turabian Style

Gastaldi, Simone, Valentina Boscaro, Eleonora Gianquinto, Christina F. Sandall, Marta Giorgis, Elisabetta Marini, Federica Blua, Margherita Gallicchio, Francesca Spyrakis, Justin A. MacDonald, and et al. 2021. "Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor" Molecules 26, no. 13: 3975. https://doi.org/10.3390/molecules26133975

APA Style

Gastaldi, S., Boscaro, V., Gianquinto, E., Sandall, C. F., Giorgis, M., Marini, E., Blua, F., Gallicchio, M., Spyrakis, F., MacDonald, J. A., & Bertinaria, M. (2021). Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor. Molecules, 26(13), 3975. https://doi.org/10.3390/molecules26133975

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