Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5′-O-aminoribosyluridine as MraY inhibitors

It is important to understand and control the biologically active conformation in medicinal chemistry. Muraymycins and caprazamycins, which are strong inhibitors of MraY, are promising antibacterial agents with a novel mode of action. Focusing on a sugar puckering and a dihedral angle ϕ of the uridine moiety of these natural products, LNA/BNA-type 5′-O-aminoribosyluridine analogues, whose puckering of the ribose moiety are completely restricted to the N-type, were designed and synthesized as simplified MraY inhibitors. Their conformation-activity relationship was further investigated in details. The conformation-activity relationship analysis investigated in this study could be a general guideline for simplification and rational drug design of MraY inhibitory nucleoside natural products.