20.500.12556/RUL-134708 Bromo-cyclobutenaminones as new covalent UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) inhibitors 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. covalent inhibitor MurA cyclobutenaminone antibacterial irreversible zaviralci MurA antibakterijske učinkovine zdravila farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2022-01-27 09:38:42 2022-01-27 09:38:45 2022-09-14 04:09:27 0000-00-00 00:00:00 2020 0 0 14 str. iss. 11, art. 362 Vol. 13 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1424-8247 10.3390/ph13110362 46907907 RAZ_Hamilton_David_J._2020.pdf RAZ_Hamilton_David_J._2020.pdf 1 ECBBB2D80D47D6766ABC0ADEEA97678B 338879b11e9a73d7dcb1002693ec8cd72fa9b7fbe560a4dce331df8020fc6944 acc0384d-7f4c-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=153296 https://www.mdpi.com/1424-8247/13/11/362 1 563c0243-7f4c-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=153294 Fakulteta za farmacijo 0 0 0