Glycomimetic Inhibitors of Mycobacterial Glycosyltransferases: Targeting the TB Cell Wall

Tuberculosis (TB) is the cause of more than a million deaths a year and is believed to infect a third of the world’s population. Emergent multidrug-resistant strains of Mycobacterium tuberculosis, the organism that causes the disease, and difficulties in treating immunocompromised individuals have further increased the urgency of the threat. The cell wall of mycobacteria is formed by polysaccharides and lipids essential for cell growth and survival in the host, and the importance of its integrity is confirmed by the effectiveness of methods that disrupt cell wall biosynthesis. The major polysaccharide region is joined to peptidoglycan by the so-called bridging region, which contains a critical and unique disaccharide phosphodiester linker (Scheme 1). The presence of an l-rhamnosyl residue in this linker region is a striking drug target opportunity, as it is a sugar that is not found in mammalian cells. A key step in the proposed biosynthetic pathway of the bacterial cell wall 10] is the rhamnosyltransferase-mediated (RhamT) glycosylation of GlcNAc-diphosphoprenyl acceptor by the dTDP-Rha donor. Since this class of enzyme is not found in man, RhamT inhibition is an avenue for a potentially nontoxic treatment of TB. Iminosugars have been widely studied as inhibitors of carbohydrate-processing enzymes such as glycosidases and glycosyltransferases (GTs). However, inhibition of l-rhamnosyl-processing enzymes has not been widely explored and there are no known Rham-T inhibitors. We report here a novel, ready and modular methodology to synthesise iminosugar lrhamnomimetics that are effective inhibitors of l-rhamnose processing enzymes including importantly the Mycobacterium biosynthesis of the bridging disaccharide region. Two parallel synthetic strategies (Scheme 2) allowed ready access to libraries of both aand b-pseudoanomers based on the l-rhamno-aza-C-glycoside scaffold 1. From the key divergent intermediate 3, through diastereoselective reduction or nucleophilic addition coupled with variation of the timing of substituent (R) introduction we could control both the pseudoanomeric configuration and identity of R in a wide-ranging manner. This has allowed us to map binding interactions and the effect of configuration in Rha-processing enzymes. Imine intermediates to rhamnomimetics 1aa–h and 1ba–p were readily accessed from azidocarbonyl precursors (5 and 6, respectively) through either intramolecular Staudinger aza-