Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors

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 heterocyc...

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Detalles Bibliográficos
Autores principales: Ábrányi-Balogh, Péter, Keeley, Aaron, Ferenczy, György G., Petri, László, Imre, Tímea, Grabrijan, Katarina, Hrast, Martina, Knez, Damijan, Ilaš, Janez, Gobec, Stanislav, Keserű, György M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781958/
https://www.ncbi.nlm.nih.gov/pubmed/36558935
http://dx.doi.org/10.3390/ph15121484
Descripción
Sumario: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.

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