Modelling, synthesis and biological evaluation of novel glucoronide-based probes of Vibrio cholerae sialidase

Abstract

The development of sialidase inhibitors is an area of continuing interest due to their potential use as therapeutic agents to combat viral and bacterial infections. Herein, we report our studies involving the sialidase from the pathogen Vibrio cholerae, through the modelling, synthesis and biological evaluation of mimetics of 5-acetamido-2,6-anhydro-3,5-dideoxy-d-glycero-d-galacto-non-2-enonic acid (Neu5Ac2en, 1), a naturally occurring sialidase inhibitor. These mimetics are O- and S-glycosides of N-acetyl-d-glucosaminuronic acid in which the aglycone portion effectively replaces the C-6 glycerol side chain of Neu5Ac2en (1). The choice of aglycones was aided by use of the X-ray crystal structure of V. cholerae sialidase complexed with Neu5Ac2en (1). All Neu5Ac2en mimetics tested were found to inhibit V. cholerae sialidase as determined using a standard fluorometric assay.