4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small lib...
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Gespeichert in:

Autor*in:	Pasquale Linciano [verfasserIn] Eleonora Gianquinto [verfasserIn] Martina Montanari [verfasserIn] Lorenzo Maso [verfasserIn] Pierangelo Bellio [verfasserIn] Esmeralda Cebrián-Sastre [verfasserIn] Giuseppe Celenza [verfasserIn] Jesús Blázquez [verfasserIn] Laura Cendron [verfasserIn] Francesca Spyrakis [verfasserIn] Donatella Tondi [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity

Übergeordnetes Werk:	In: Pharmaceuticals - MDPI AG, 2005, 13(2020), 3, p 52
Übergeordnetes Werk:	volume:13 ; year:2020 ; number:3, p 52

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/ph13030052

Katalog-ID:	DOAJ01429835X

Internformat


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allfields	10.3390/ph13030052 doi (DE-627)DOAJ01429835X (DE-599)DOAJba468f3a8a2d4b0e8be2386483fb0e6c DE-627 ger DE-627 rakwb eng RS1-441 Pasquale Linciano verfasserin aut 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. 4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity Medicine R Pharmacy and materia medica Eleonora Gianquinto verfasserin aut Martina Montanari verfasserin aut Lorenzo Maso verfasserin aut Pierangelo Bellio verfasserin aut Esmeralda Cebrián-Sastre verfasserin aut Giuseppe Celenza verfasserin aut Jesús Blázquez verfasserin aut Laura Cendron verfasserin aut Francesca Spyrakis verfasserin aut Donatella Tondi verfasserin aut In Pharmaceuticals MDPI AG, 2005 13(2020), 3, p 52 (DE-627)491437528 (DE-600)2193542-7 14248247 nnns volume:13 year:2020 number:3, p 52 https://doi.org/10.3390/ph13030052 kostenfrei https://doaj.org/article/ba468f3a8a2d4b0e8be2386483fb0e6c kostenfrei https://www.mdpi.com/1424-8247/13/3/52 kostenfrei https://doaj.org/toc/1424-8247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_73 GBV_ILN_74 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_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 13 2020 3, p 52
spelling	10.3390/ph13030052 doi (DE-627)DOAJ01429835X (DE-599)DOAJba468f3a8a2d4b0e8be2386483fb0e6c DE-627 ger DE-627 rakwb eng RS1-441 Pasquale Linciano verfasserin aut 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. 4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity Medicine R Pharmacy and materia medica Eleonora Gianquinto verfasserin aut Martina Montanari verfasserin aut Lorenzo Maso verfasserin aut Pierangelo Bellio verfasserin aut Esmeralda Cebrián-Sastre verfasserin aut Giuseppe Celenza verfasserin aut Jesús Blázquez verfasserin aut Laura Cendron verfasserin aut Francesca Spyrakis verfasserin aut Donatella Tondi verfasserin aut In Pharmaceuticals MDPI AG, 2005 13(2020), 3, p 52 (DE-627)491437528 (DE-600)2193542-7 14248247 nnns volume:13 year:2020 number:3, p 52 https://doi.org/10.3390/ph13030052 kostenfrei https://doaj.org/article/ba468f3a8a2d4b0e8be2386483fb0e6c kostenfrei https://www.mdpi.com/1424-8247/13/3/52 kostenfrei https://doaj.org/toc/1424-8247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_73 GBV_ILN_74 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_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 13 2020 3, p 52
allfields_unstemmed	10.3390/ph13030052 doi (DE-627)DOAJ01429835X (DE-599)DOAJba468f3a8a2d4b0e8be2386483fb0e6c DE-627 ger DE-627 rakwb eng RS1-441 Pasquale Linciano verfasserin aut 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. 4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity Medicine R Pharmacy and materia medica Eleonora Gianquinto verfasserin aut Martina Montanari verfasserin aut Lorenzo Maso verfasserin aut Pierangelo Bellio verfasserin aut Esmeralda Cebrián-Sastre verfasserin aut Giuseppe Celenza verfasserin aut Jesús Blázquez verfasserin aut Laura Cendron verfasserin aut Francesca Spyrakis verfasserin aut Donatella Tondi verfasserin aut In Pharmaceuticals MDPI AG, 2005 13(2020), 3, p 52 (DE-627)491437528 (DE-600)2193542-7 14248247 nnns volume:13 year:2020 number:3, p 52 https://doi.org/10.3390/ph13030052 kostenfrei https://doaj.org/article/ba468f3a8a2d4b0e8be2386483fb0e6c kostenfrei https://www.mdpi.com/1424-8247/13/3/52 kostenfrei https://doaj.org/toc/1424-8247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_73 GBV_ILN_74 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_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 13 2020 3, p 52
allfieldsGer	10.3390/ph13030052 doi (DE-627)DOAJ01429835X (DE-599)DOAJba468f3a8a2d4b0e8be2386483fb0e6c DE-627 ger DE-627 rakwb eng RS1-441 Pasquale Linciano verfasserin aut 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. 4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity Medicine R Pharmacy and materia medica Eleonora Gianquinto verfasserin aut Martina Montanari verfasserin aut Lorenzo Maso verfasserin aut Pierangelo Bellio verfasserin aut Esmeralda Cebrián-Sastre verfasserin aut Giuseppe Celenza verfasserin aut Jesús Blázquez verfasserin aut Laura Cendron verfasserin aut Francesca Spyrakis verfasserin aut Donatella Tondi verfasserin aut In Pharmaceuticals MDPI AG, 2005 13(2020), 3, p 52 (DE-627)491437528 (DE-600)2193542-7 14248247 nnns volume:13 year:2020 number:3, p 52 https://doi.org/10.3390/ph13030052 kostenfrei https://doaj.org/article/ba468f3a8a2d4b0e8be2386483fb0e6c kostenfrei https://www.mdpi.com/1424-8247/13/3/52 kostenfrei https://doaj.org/toc/1424-8247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_73 GBV_ILN_74 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_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 13 2020 3, p 52
allfieldsSound	10.3390/ph13030052 doi (DE-627)DOAJ01429835X (DE-599)DOAJba468f3a8a2d4b0e8be2386483fb0e6c DE-627 ger DE-627 rakwb eng RS1-441 Pasquale Linciano verfasserin aut 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. 4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity Medicine R Pharmacy and materia medica Eleonora Gianquinto verfasserin aut Martina Montanari verfasserin aut Lorenzo Maso verfasserin aut Pierangelo Bellio verfasserin aut Esmeralda Cebrián-Sastre verfasserin aut Giuseppe Celenza verfasserin aut Jesús Blázquez verfasserin aut Laura Cendron verfasserin aut Francesca Spyrakis verfasserin aut Donatella Tondi verfasserin aut In Pharmaceuticals MDPI AG, 2005 13(2020), 3, p 52 (DE-627)491437528 (DE-600)2193542-7 14248247 nnns volume:13 year:2020 number:3, p 52 https://doi.org/10.3390/ph13030052 kostenfrei https://doaj.org/article/ba468f3a8a2d4b0e8be2386483fb0e6c kostenfrei https://www.mdpi.com/1424-8247/13/3/52 kostenfrei https://doaj.org/toc/1424-8247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_73 GBV_ILN_74 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_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 13 2020 3, p 52
language	English
source	In Pharmaceuticals 13(2020), 3, p 52 volume:13 year:2020 number:3, p 52
sourceStr	In Pharmaceuticals 13(2020), 3, p 52 volume:13 year:2020 number:3, p 52
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authorswithroles_txt_mv	Pasquale Linciano @@aut@@ Eleonora Gianquinto @@aut@@ Martina Montanari @@aut@@ Lorenzo Maso @@aut@@ Pierangelo Bellio @@aut@@ Esmeralda Cebrián-Sastre @@aut@@ Giuseppe Celenza @@aut@@ Jesús Blázquez @@aut@@ Laura Cendron @@aut@@ Francesca Spyrakis @@aut@@ Donatella Tondi @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
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callnumber-first	R - Medicine
author	Pasquale Linciano
spellingShingle	Pasquale Linciano misc RS1-441 misc 4-amino-1,2,4-triazole-3-thione misc bacterial resistance misc structure-based drug design misc non-covalent inhibition misc thione/thiol tautomerism misc broad-spectrum activity misc Medicine misc R misc Pharmacy and materia medica 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases
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topic_title	RS1-441 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases 4-amino-1,2,4-triazole-3-thione bacterial resistance structure-based drug design non-covalent inhibition thione/thiol tautomerism broad-spectrum activity
topic	misc RS1-441 misc 4-amino-1,2,4-triazole-3-thione misc bacterial resistance misc structure-based drug design misc non-covalent inhibition misc thione/thiol tautomerism misc broad-spectrum activity misc Medicine misc R misc Pharmacy and materia medica
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title	4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases
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title_full	4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases
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title_sort	4-amino-1,2,4-triazole-3-thione as a promising scaffold for the inhibition of serine and metallo-<i<β</i<-lactamases
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title_auth	4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases
abstract	The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.
abstractGer	The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.
abstract_unstemmed	The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i<β</i<-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i<β</i<-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i<β−</i<Lactamase (SBLs) KPC-2 and class B1 metallo <i<β−</i<Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i<in silico</i< analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.
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title_short	4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases
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4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i<β</i<-Lactamases

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