Next-generation heterocyclic electrophiles as small-molecule covalent MurA inhibitors

Ábrányi-Balogh, Péter (author), Keeley, Aaron (author), Ferenczy, György G. (author), Petri, László (author), Imre, Tímea (author), Grabrijan, Katarina (author), Hrast, Martina (author), Knez, Damijan (author), Ilaš, Janez (author), Gobec, Stanislav (author), Keserü M., György (author)

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
• UDC: 615.4:54:615.28
• ISSN on article: 1424-8247
• DOI: 10.3390/ph15121484
• COBISS.SI-ID: 132462339
• Publication date in RUL: 06.12.2022

Record is a part of a journal

• Title: Pharmaceuticals
• Shortened title: Pharmaceuticals
• Publisher: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

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