title: Synthesis of a poly-hydroxypyrolidine-based inhibitor of Mycobacterium tuberculosis GlgE.
abstract: Long treatment times, poor drug compliance, and natural selection during treatment of Mycobacterium tuberculosis (Mtb) have given rise to extensively drug-resistant tuberculosis (XDR-TB). As a result, there is a need to identify new antituberculosis drug targets. Mtb GlgE is a maltosyl transferase involved in α-glucan biosynthesis. Mutation of GlgE in Mtb increases the concentration of maltose-1-phosphate (M1P), one substrate for GlgE, causing rapid cell death. We have designed 2,5-dideoxy-3-O-α-d-glucopyranosyl-2,5-imino-d-mannitol (9) to act as an inhibitor of GlgE. Compound 9 was synthesized using a convergent synthesis by coupling thioglycosyl donor 14 and 5-azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (23) to form disaccharide 24. A reduction and intramolecular reductive amination transformed the intermediate disaccharide 24 to the desired pyrolidine 9. Compound 9 inhibited both Mtb GlgE and a variant of Streptomyces coelicolor (Sco) GlgEI with Ki = 237 ± 27 μM and Ki = 102 ± 7.52 μM, respectively. The results confirm that a Sco GlgE-V279S variant can be used as a model for Mtb GlgE. In conclusion, we designed a lead transition state inhibitor of GlgE, which will be instrumental in further elucidation of the enzymatic mechanism of Mtb GlgE.
authors.affiliation: Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo , 2801 West Bancroft Street, Toledo, Ohio 43606, United States.
authors.forename: Sri Kumar
authors.initials: SK
authors.lastname: Veleti
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Lindenberger
authors.forename: Sandeep
authors.initials: S
authors.lastname: Thanna
authors.forename: Donald R
authors.initials: DR
authors.lastname: Ronning
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sucheck
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005936:Glucans / Q000096:biosynthesis* / Q000737:chemistry*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D013403:Sugar Phosphates / Q000737:chemistry*
chemical_list: C000597333:2,5-dideoxy-3-O-alpha-D-glucopyranosyl-2,5-imino-D-mannitol; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004187:Disaccharides; D004791:Enzyme Inhibitors; D005936:Glucans; D013403:Sugar Phosphates; C080751:maltose 1-phosphate; D005964:Glucosyltransferases; C436710:maltosyltransferase