Synthesis and Biological Evaluation of Non‐Hydrolyzable 1,2,3‐Triazole‐Linked Sialic Acid Derivatives as Neuraminidase Inhibitors

Abstract

α-Sialic acid azide <b>1</b> has been used as a substrate for the efficient preparation of 1,2,3-triazole derivatives of sialic acid using the copper-catalyzed azide-alkyne Huisgen cycloaddition ("click chemistry"). Our approach is to generate non-natural <i>N</i>-glycosides of sialic acid that are resistant to neuraminidase catalyzed hydrolysis as opposed to the natural <i>O</i>-glycosides. These <i>N</i>-glycosides would act as neuraminidase inhibitors to prevent the release of new virions. As a preliminary study, a small library of 1,2,3-triazole-linked sialic acid derivatives has been synthesized in 71-89% yield. A disaccharide mimic of sialic acid has also been prepared using the α-sialic acid azide <b>1</b> and a C-8 propargyl sialic acid acceptor in 68% yield. A model sialic acid coated dendrimer was also synthesized from a per-propargylated pentaerythritol acceptor. These novel sialic acid derivatives were then evaluated as potential neuraminidase inhibitors using a 96-well plate fluorescence assay; micromolar IC₅₀ values were observed, comparable to the known sialidase inhibitor Neu5Ac2en.