Novel inhibitors of human intestinal N-terminal maltase-glucoamylase and influenza virus A neuraminidase

This thesis work deals with the syntheses and biological evaluation of novel inhibitors of two clinically relevant glycosidases, namely, human intestinal N-terminal maltase-glucoamylase (ntMGAM) and influenza virus neuraminidase (NA, also known as sialidase). Kotalanol, a naturally-occurring sulfonium-ion glucosidase inhibitor isolated from Salacia reticulata, with potent inhibitory activities against rat intestinal glucosidases, has potential to become a lead candidate in the treatment of type 2 diabetes. However, the lack of information about its stereostructure posed a major challenge for its total synthesis and structure-activity relationship studies. In this thesis, we successfully established the absolute stereostructure of kotalanol and also completed its total synthesis and that of its de-O-sulfonated derivative. The synthetic route was also extended to obtain heteroatom analogues and the six-membered ring nitrogen analogues of kotalanol and their de-O-sulfonated derivatives, and the inhibitory activities of these compounds were studied against ntMGAM. Neuraminidase, a glycoprotein located on the surface of the influenza virus, plays a crucial role in the viral replication process and hence, has proven to be a useful target enzyme for the treatment of influenza infections. The X-ray crystal structures of certain subtypes of influenza group-1 neuraminidases (N1, N4 and N8 subtypes) revealed that there exists a cavity (known as the 150-cavity) near the active-site resulting from a loop of amino acid residues (known as the 150-loop) that adopts an unusual open-loop conformation. Accordingly, we report here the exploitation of the 150-cavity in the active-sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (N1) activity indicate that several candidates are inhibitors, with Ki values in the 10-5 - 10-8 M range. The proposed binding model for the triazole series of compounds was confirmed using the X-ray crystallographic analysis of the N8 subtype complexed with two compounds from the triazole series. We have also assessed the crossreactivity of these novel inhibitors against human neuraminidase isoform-3 (NEU3) as well as their ability to inhibit the replication of two different strains of influenza virus A in vitro using a cell-based assay.