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Next-generation heterocyclic electrophiles as small-molecule covalent MurA inhibitors
ID Ábrányi-Balogh, Péter (Author), ID Keeley, Aaron (Author), ID Ferenczy, György G. (Author), ID Petri, László (Author), ID Imre, Tímea (Author), ID Grabrijan, Katarina (Author), ID Hrast, Martina (Author), ID Knez, Damijan (Author), ID Ilaš, Janez (Author), ID Gobec, Stanislav (Author), ID Keserü M., György (Author)

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Abstract
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.

Language:English
Keywords:covalent inhibitor, heterocyclic electrophiles, cysteine labelling, quaternization, MurA
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Publication status:Published
Publication version:Version of Record
Year:2022
Number of pages:10 str.
Numbering:Vol. 15, iss. 12, art. 1484
PID:20.500.12556/RUL-142958 This link opens in a new window
UDC:615.4:54:615.28
ISSN on article:1424-8247
DOI:10.3390/ph15121484 This link opens in a new window
COBISS.SI-ID:132462339 This link opens in a new window
Publication date in RUL:06.12.2022
Views:640
Downloads:46
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Record is a part of a journal

Title:Pharmaceuticals
Shortened title:Pharmaceuticals
Publisher:MDPI
ISSN:1424-8247
COBISS.SI-ID:517582617 This link opens in a new window

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

Language:Slovenian
Keywords:kovalentni inhibitor, heterociklični elektrofili, označevanje cisteina, kvaternizacija, MurA

Projects

Funder:ARRS - Slovenian Research Agency
Project number:N1-0169-2021
Name:Kovalentni pristop k boju proti bakterijski rezistenci
Funder:ARRS - Slovenian Research Agency
Project number:J1-2484-2020
Name:Razvoj protibakteriskih učinkovin z delovanjem na validirane tarče v biosintezi peptidoglikana
Funder:EC - European Commission
Funding programme:European Commission
Project number:675899
Name:FRAGments training NETwork
Acronym:FRAGNET
Funder:Other - Other funder or multiple funders
Funding programme:National Research Development and Innovation Office
Project number:SNN-13533
Funder:Other - Other funder or multiple funders
Funding programme:National Research Development and Innovation Office
Project number:SNN_17 125496
Name:2018-2.1.11-TÉT-SI-2018-00005
Funder:Other - Other funder or multiple funders
Funding programme:National Research Development and Innovation Office
Project number:PD124598
Funder:Other - Other funder or multiple funders
Funding programme:National Research Development and Innovation Office

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