Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis which is a lethal disease. It is among the top 10 causes of death worldwide and the leading cause of death from a single infectious disease. Mtb has been shown to develop resistance to the current drugs thereby, demanding the investigation of potential drug targets. GlgE is an essential α-glycoside hydrolase (α-GH) which is responsible for catalyzing the addition of maltose-1-phosphate (M1P) to maltooligosaccharides. Inhibiting the activity of this enzyme leads to the death of the Mtb cell due to excessive accumulation of M1P. Our group has been working on designing and synthesizing potential covalent and non-covalent inhibitors against Mtb GlgE. We have developed a robust method in the lab for synthesizing these targets. Previously, we synthesized and evaluated the inhibitory activity of amine-based carbasugars. In this work, we continue our investigation of the maltose scaffold by the introduction of 1,3,5-trifluorobenzene leaving group into the pseudoanomeric position of the maltose derivatives modified with either a valieol-like moiety or a cyclopropane containing carbasugar. We assumed two different protecting groups for our synthetic strategy, benzyl and bromobenzyl to afford the desired cyclopropyl and valieol-based targets respectively. Our maltoside derivatives are obtained from intermediates (benzyl and bromobenzyl protected) which were prepared in 10 steps involving Wittig olefination, Moffatt’s oxidation, Grignard reaction, Grubbs’ ring closing metathesis reaction and acetyl assisted Pd catalyzed rearrangement reaction. The benzyl carbasugar intermediate was then subjected to Simmons-Smith cyclopropane reaction followed by nucleophilic aromatic substitution using 1,3,5 trifluorobenzene. The obtained product was hydrogenated to afford the desired cyclopropane carbasugar target. The bromobenzyl carbasugar was subjected to 1,3,5 trifluorobenzene to yield a valieol-like intermediate. Using Buchwald-Hartwig amination, the bromobenzyl group was converted to an acid-labile amine group, the deprotection of which led to the desired cyclohexene or valieol-like carbasugar. Both the targets are currently being assessed for their inhibitory activity and further investigation will be conducted once the results have been evaluated.

Synthesizing and investigating the inhibitory activity of potential maltoside inhibitors for Mtb.GlgE

ACS Spring 2022

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