Tuberculosis is a fatal disease caused by Mycobacterium tuberculosis(Mtb).This bacterium has been shown to develop resistance to the current drugs thereby, demanding the investigation of potential drug targets.Mtb.GlgE is an essential α-glycoside hydrolase like enzyme which is responsible for catalyzing the addition of maltose-1-phosphate (M1P) to maltooligosaccharides that assist in the building of the cell wall. Inhibiting the activity of this enzyme leads to the death of the Mtbcell due to the accumulation of M1P. Carbasugars with leaving groups at the pseudo-anomeric hydroxyl such as p-nitro benzene are known potent covalent inhibitors of glycoside hydrolases. Bearing this in mind, we synthesized carbasugars starting from glucose derivatives. p-Tolylβ-thioglucoside 1 was subjected to oxidizing conditions to obtain a free reducing end on the sugar. Wittig olefination was performed using methyltriphenylphosphonium bromide, the resulting secondary alcohol (~75%) was subjected to Moffatt oxidation to yield a ketone (&gt;95%). Addition into the carbonyl with vinyl magnesium bromide gave two separable diastereomers in 8:1 ratio (~80% mixture). Ring-closing metathesis using Grubb’s 1stgeneration catalyst afforded the desired carbasugar (82%). The tertiary free hydroxy was rearranged using bis-acetonitrile palladium (II) chloride catalyst via acetyl protection (&gt;95%). Subsequent nucleophilic substitution with 1,3,5 trifluorobenzene (&gt;92%) followed by global deprotection yielded the desired carbasugar 2with a leaving group to facilitate a covalent binding interaction with the enzyme. The obtained glucose analog will be chemoenzymatically glycosylated using reported literature to yield a disaccharide analog mimicking the GlgE substrate M1P. The synthesized monosaccharide and disaccharide will be evaluated for inhibitory activity against Mtb GlgE.

Synthesis of potential carbasugar-based covalent inhibitors of Mycobacterium tuberculosis GlgE

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.