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

Povzetek

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.

Ključne besede

covalent inhibitor;MurA;cyclobutenaminone;antibacterial;irreversible;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.4:54
COBISS: 46907907 Povezava se bo odprla v novem oknu
ISSN: 1424-8247
Št. ogledov: 128
Št. prenosov: 64
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: zaviralci MurA;antibakterijske učinkovine;Zdravila;Farmacevtska kemija;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-14
Letnik: ǂVol. ǂ13
Zvezek: ǂiss. ǂ11
Čas izdaje: 2020
DOI: 10.3390/ph13110362
ID: 14373095