Mechanism-based candidate inhibitors of galactopyranose mutase

The synthesis of candidate inhibitors of Mycobacterium tuberculosis cell-wall biosynthesis as potential therapeutic agents for the treatment of tuberculosis is presented. A critical component of the cell wall of M. tuberculosis is a D-galactan polymer, a polysaccharide chain consisting of D-galactofuranose (Galf) residues. Since Galf residues are not found in mammalian systems, inhibition of the biosynthesis of this polymer constitutes a very attractive and accessible target for new anti-TB drugs. A critical enzyme required for the biosynthesis of the galactan polymer is uridine diphosphate galactopyranose mutase (UGM), which catalyzes the interconversion of UDP-galactopyranose (Galp) and UDP-galactofuranose (Galf). The goal of the project was to synthesize compounds that inhibit growth of the cell wall by compromising the activity of the UGM enzyme. The compounds were intended to mimic not only the positive charge character of the galactopyranosyl cation (transition state in the UGM-catalyzed reaction) but also its shape (proposed 4H3 conformation).