Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors

Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyc...

Descripción completa

Detalles Bibliográficos
Autores principales: Ábrányi-Balogh, Péter, Keeley, Aaron, Ferenczy, György G., Petri, László, Imre, Tímea, Grabrijan, Katarina, Hrast, Martina, Knez, Damijan, Ilaš, Janez, Gobec, Stanislav, Keserű, György M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781958/
https://www.ncbi.nlm.nih.gov/pubmed/36558935
http://dx.doi.org/10.3390/ph15121484
_version_ 1784857201827905536
author Ábrányi-Balogh, Péter
Keeley, Aaron
Ferenczy, György G.
Petri, László
Imre, Tímea
Grabrijan, Katarina
Hrast, Martina
Knez, Damijan
Ilaš, Janez
Gobec, Stanislav
Keserű, György M.
author_facet Ábrányi-Balogh, Péter
Keeley, Aaron
Ferenczy, György G.
Petri, László
Imre, Tímea
Grabrijan, Katarina
Hrast, Martina
Knez, Damijan
Ilaš, Janez
Gobec, Stanislav
Keserű, György M.
author_sort Ábrányi-Balogh, Péter
collection PubMed
description Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyclic covalent fragment library with improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH (L-glutathione) reactivity assay, and thrombin counter screen were also used to demonstrate and explain the improved reactivity and selectivity of the N-methylated heterocycles and to compare the two generations of heterocyclic electrophiles.
format Online
Article
Text
id pubmed-9781958
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97819582022-12-24 Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors Ábrányi-Balogh, Péter Keeley, Aaron Ferenczy, György G. Petri, László Imre, Tímea Grabrijan, Katarina Hrast, Martina Knez, Damijan Ilaš, Janez Gobec, Stanislav Keserű, György M. Pharmaceuticals (Basel) Article Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyclic covalent fragment library with improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH (L-glutathione) reactivity assay, and thrombin counter screen were also used to demonstrate and explain the improved reactivity and selectivity of the N-methylated heterocycles and to compare the two generations of heterocyclic electrophiles. MDPI 2022-11-29 /pmc/articles/PMC9781958/ /pubmed/36558935 http://dx.doi.org/10.3390/ph15121484 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ábrányi-Balogh, Péter
Keeley, Aaron
Ferenczy, György G.
Petri, László
Imre, Tímea
Grabrijan, Katarina
Hrast, Martina
Knez, Damijan
Ilaš, Janez
Gobec, Stanislav
Keserű, György M.
Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
title Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
title_full Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
title_fullStr Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
title_full_unstemmed Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
title_short Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
title_sort next-generation heterocyclic electrophiles as small-molecule covalent mura inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781958/
https://www.ncbi.nlm.nih.gov/pubmed/36558935
http://dx.doi.org/10.3390/ph15121484
work_keys_str_mv AT abranyibaloghpeter nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT keeleyaaron nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT ferenczygyorgyg nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT petrilaszlo nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT imretimea nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT grabrijankatarina nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT hrastmartina nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT knezdamijan nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT ilasjanez nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT gobecstanislav nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors
AT keserugyorgym nextgenerationheterocyclicelectrophilesassmallmoleculecovalentmurainhibitors

Ejemplares similares