Degree: Master of Science Abstract: Sialidase enzymes play an important role in regulation of cellular activities by hydrolyzing the terminal, non-reducing sialic acids attached to various glycolipids, glycoproteins, and gangliosides. The family of human sialidase enzymes, NEU1, NEU2, NEU3, and NEU4 contribute specifically to different cellular processes. In particular, the plasma membrane associated sialidase NEU3 was studied by our group due to its specificity for glycolipids and its proposed role in cell signaling. This thesis describes the design and synthesis of sialidase inhibitors based on the 2,3-didehydro-N-acetyl neuraminic acid scaffold. Specific inhibitors of these enzymes will allow us to explore their function in vivo. In Chapter 2 we describe a series of C9 and N5Ac modified analogs of DANA (2,3-Didehydro-2-deoxy-N-acetylneuraminic acid) which were designed, synthesized and biologically evaluated. Molecular docking experiments revealed NEU3 can tolerate large hydrophobic groups at the C9 position, however, N5Ac derivatives failed to inhibit NEU3. This result suggested that glycerol side-chain modified derivatives of DANA could prove to be potent inhibitors of the enzyme. In Chapter 3 we develop a synthetic route to generate a series of C7-modified DANA derivatives. We isolated several C7-hydrazone derivatives that will be tested against human neuraminidase enzymes as inhibitors. The results from these studies provided valuable insight regarding the interaction of small molecule inhibitors with the active site of the human NEU3 enzyme, and have improved synthetic strategies towards DANA derivatives that may take advantage of the unique active site topology of NEU3.