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

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-2<i<H</i<-benzo[d]imidazole-2-one substructure pres...
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Autor*in:	Simone Gastaldi [verfasserIn] Valentina Boscaro [verfasserIn] Eleonora Gianquinto [verfasserIn] Christina F. Sandall [verfasserIn] Marta Giorgis [verfasserIn] Elisabetta Marini [verfasserIn] Federica Blua [verfasserIn] Margherita Gallicchio [verfasserIn] Francesca Spyrakis [verfasserIn] Justin A. MacDonald [verfasserIn] Massimo Bertinaria [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 26(2021), 13, p 3975
Übergeordnetes Werk:	volume:26 ; year:2021 ; number:13, p 3975

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules26133975

Katalog-ID:	DOAJ052372944

Internformat


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allfields	10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975
spelling	10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975
allfields_unstemmed	10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975
allfieldsGer	10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975
allfieldsSound	10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975
language	English
source	In Molecules 26(2021), 13, p 3975 volume:26 year:2021 number:13, p 3975
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topic_facet	NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry
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authorswithroles_txt_mv	Simone Gastaldi @@aut@@ Valentina Boscaro @@aut@@ Eleonora Gianquinto @@aut@@ Christina F. Sandall @@aut@@ Marta Giorgis @@aut@@ Elisabetta Marini @@aut@@ Federica Blua @@aut@@ Margherita Gallicchio @@aut@@ Francesca Spyrakis @@aut@@ Justin A. MacDonald @@aut@@ Massimo Bertinaria @@aut@@
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callnumber-first	Q - Science
author	Simone Gastaldi
spellingShingle	Simone Gastaldi misc QD241-441 misc NLRP3 inhibitors misc pyroptosis misc interleukin-1β misc ATP hydrolysis misc MD simulations misc Organic chemistry Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
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topic_title	QD241-441 Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations
topic	misc QD241-441 misc NLRP3 inhibitors misc pyroptosis misc interleukin-1β misc ATP hydrolysis misc MD simulations misc Organic chemistry
topic_unstemmed	misc QD241-441 misc NLRP3 inhibitors misc pyroptosis misc interleukin-1β misc ATP hydrolysis misc MD simulations misc Organic chemistry
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title	Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
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title_full	Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
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author_browse	Simone Gastaldi Valentina Boscaro Eleonora Gianquinto Christina F. Sandall Marta Giorgis Elisabetta Marini Federica Blua Margherita Gallicchio Francesca Spyrakis Justin A. MacDonald Massimo Bertinaria
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title_sort	chemical modulation of the 1-(piperidin-4-yl)-1,3-dihydro-2<i<h</i<-benzo[d]imidazole-2-one scaffold as a novel nlrp3 inhibitor
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title_auth	Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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.
abstractGer	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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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.
abstract_unstemmed	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-2<i<H</i<-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 <b<9</b<, <b<13</b< and <b<18</b<, 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.
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container_issue	13, p 3975
title_short	Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
url	https://doi.org/10.3390/molecules26133975 https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 https://www.mdpi.com/1420-3049/26/13/3975 https://doaj.org/toc/1420-3049
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author2	Valentina Boscaro Eleonora Gianquinto Christina F. Sandall Marta Giorgis Elisabetta Marini Federica Blua Margherita Gallicchio Francesca Spyrakis Justin A. MacDonald Massimo Bertinaria
author2Str	Valentina Boscaro Eleonora Gianquinto Christina F. Sandall Marta Giorgis Elisabetta Marini Federica Blua Margherita Gallicchio Francesca Spyrakis Justin A. MacDonald Massimo Bertinaria
ppnlink	311313132
callnumber-subject	QD - Chemistry
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isOA_txt	true
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doi_str	10.3390/molecules26133975
callnumber-a	QD241-441
up_date	2024-07-04T00:48:48.412Z
_version_	1803607477754789888
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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 <b<9</b<, <b<13</b< and <b<18</b<, 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. 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Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

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