Synthesis and biological evaluation of a diazepanone-based library of liposidomycins analogs as MraY inhibitors

New inhibitors of the bacterial tranferase MraY are described. A scaffold strategy based on the diazepanone central core of liposidomycins, natural inhibitors of MraY has been developed. It involves the introduction of key structural fragments required for biological activity on enantiopure diazepanones by reductive amination, esterification and glycosylation. Biological evaluation of these compounds on MraY enzyme revealed interesting inhibitory activity for compounds displaying three fragments on the scaffold: a palmitoyl chain, an aminoribose part and an alkyluracil moiety. The inhibitors were also evaluated on MurG enzyme. The best compounds resulted in inhibition with IC50 values in the 100 μM range for one or the other enzyme.

A straightforward route toward new MraY inhibitors is described. A scaffold strategy based on highly functionalized diazepanone platforms is developed. Biological evaluation of the compounds is reported.Figure optionsDownload as PowerPoint slideHighlights
► A scaffold strategy was developed toward a library of MraY inhibitors.
► A diazepanone scaffold, central core of natural MraY inhibitors, was chosen.
► Fatty acid, alkyluracil and aminoribose were introduced on the scaffold.
► Biological evaluation showed inhibition of MraY activity with IC50 in the 100 μM range.