Synthesis of a poly-hydroxypyrolidine-based inhibitor of Mycobacterium tuberculosis GlgE.
J Org Chem
; 79(20): 9444-50, 2014 Oct 17.
Article
em En
| MEDLINE
| ID: mdl-25137149
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-ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Fosfatos Açúcares
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Proteínas de Bactérias
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Farmacorresistência Bacteriana
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Dissacarídeos
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Glucanos
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Glucosiltransferases
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Mycobacterium tuberculosis
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Antituberculosos
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article