Mycobacterium tuberculosis (Mtb) is an etiological agent of Tuberculosis (TB), a disease that kills approximately 1.5 million people annually. There is great need to identify more effective anti-TB therapies in order to eradicate the disease. Mtb GlgE is a glycoside hydrolase-like phosphatase involved in Mtb α-glucan biosynthesis and is a genetically validated Mtb drug target. We have designed transition state inhibitors against both Mtb GlgE and a closely related homolog, S. coelicolor (Sco) GlgEI-V279S. Previously, we have reported that pyrrolidines, which act as transition state mimics, inhibit both isoforms of the enzyme at mid-micromolar concentrations. However, pyrrolidines only mimic a portion of the first transition state catalyzed by GlgE. We proposed that we could improve the inhibitor design by incorporating a phosphonate moiety into pyrrolidines which could mimic the phosphate that leaves in the first step of the enzymatic reaction. We employed aza-Micheal, Kabachnik–Fields and reductive amination approaches to prepare various pyrrolidine N-alkyl-phosphonates. The resulting compounds showed Kis in the range of 45-96 uM , a two-fold improvement in enzyme inhibition over previously reported compounds.

Synthesis of pyrrolidine N-alkyl-phosphonates: Transition state inhibitors of S. coelicolor GlgEI-V279S

251st National Meeting (2016)

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