Bromo-cyclobutenaminones as new covalent UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) inhibitors

Hamilton, David J. (author), Ábrányi-Balogh, Péter (author), Keeley, Aaron (author), Petri, László (author), Hrast, Martina (author), Imre, Tímea (author), Wijtmans, Maikel (author), Gobec, Stanislav (author), de Esch, Iwan J. P. (author), Keserü M., György (author)

Drug discovery programs against the antibacterial target UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads. The electrophilic reactivity and cysteine specificity have been determined in a glutathione (GSH) and an oligopeptide assay, respectively. Investigating the structure-activity relationship for MurA suggests a crucial role for the bromine atom in the ligand. In addition, MS/MS experiments have proven the covalent labelling of MurA at Cys115 and the observed loss of the bromine atom suggests a net nucleophilic substitution as the covalent reaction. This new set of compounds might be considered as a viable chemical starting point for the discovery of new MurA inhibitors.

• Language: English
• Keywords: covalent inhibitor, MurA, cyclobutenaminone, antibacterial, irreversible
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 14 str.
• Numbering: Vol. 13, iss. 11, art. 362
• PID: 20.500.12556/RUL-134708
• UDC: 615.4:54
• ISSN on article: 1424-8247
• DOI: 10.3390/ph13110362
• COBISS.SI-ID: 46907907
• Publication date in RUL: 27.01.2022

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.
• Licensing start date: 03.11.2020

Secondary language

• Language: Slovenian
• Keywords: zaviralci MurA, antibakterijske učinkovine, zdravila, farmacevtska kemija