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

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

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.

• Jezik: Angleški jezik
• Ključne besede: covalent inhibitor, MurA, cyclobutenaminone, antibacterial, irreversible
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: 14 str.
• Številčenje: Vol. 13, iss. 11, art. 362
• PID: 20.500.12556/RUL-134708
• UDK: 615.4:54
• ISSN pri članku: 1424-8247
• DOI: 10.3390/ph13110362
• COBISS.SI-ID: 46907907
• Datum objave v RUL: 27.01.2022

Gradivo je del revije

• Naslov: Pharmaceuticals
• Skrajšan naslov: Pharmaceuticals
• Založnik: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 03.11.2020

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci MurA, antibakterijske učinkovine, zdravila, farmacevtska kemija