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A Sub-Micromolar MraY(AA) Inhibitor with an Aminoribosyl Uridine Structure and a (S,S)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synth...

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Detalles Bibliográficos
Autores principales: Oliver, Martin, Le Corre, Laurent, Poinsot, Mélanie, Bosco, Michaël, Wan, Hongwei, Amoroso, Ana, Joris, Bernard, Bouhss, Ahmed, Calvet-Vitale, Sandrine, Gravier-Pelletier, Christine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954382/
https://www.ncbi.nlm.nih.gov/pubmed/35335131
http://dx.doi.org/10.3390/molecules27061769
Descripción
Sumario:New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraY(AA) transferase activity, and the most active compound with an original (S,S)-tartaric diamide linker inhibits MraY activity with an IC(50) equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.