Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphate analogues as chelation-based inhibitors of methylerythritol phosphate synthase.
[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.
Walker
Joel R
JR
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Poulter
C Dale
CD
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010428:Pentosephosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C109460:1-deoxylulose 5-phosphate; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010428:Pentosephosphates; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases