Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphate analogues as chelation-based inhibitors of methylerythritol phosphate synthase

The Journal of Organic Chemistry
Joel R Walker, C D Poulter

Abstract

[structures: see text] A series of 1-deoxy-D-xylulose 5-phosphate (DXP) analogues were synthesized and evaluated as inhibitors of E. coli methylerythritol phosphate (MEP) synthase. In analogues 1-4, the methyl group in DXP was replaced by hydroxyl, hydroxylamino, methoxy, and amino moieties, respectively. In analogues 5 and 6, the acetyl moiety in DXP was replaced by hydroxymethyl and aminomethyl groups. These compounds were designed to coordinate to the active site divalent metal in MEP synthase. The carboxylate (1), methyl ester (3), amide (4), and alcohol (5) analogues were inhibitors with IC50's ranging from 0.25 to 1.0 mM. The hydroxamic acid (2) and amino (6) analogues did not inhibit the enzyme.

Related Concepts

1-deoxy-D-xylulose 5-phosphate
YaeM protein, E coli
Metal Antagonists
Enzyme Inhibitors
Multienzyme Complexes
Oxidase
Pentosephosphates
Protein Conformation
Molecular Stereochemistry
Structure-Activity Relationship

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