Functionalized 3,5-dihydroxybenzoates as potent novel inhibitors of EPSP synthase.
Aromatic analogues of the EPSP synthase enzyme substrate (S3P), reaction intermediate (1), and product (EPSP) were synthesized from 3,5-dihydroxybenzoic acid and were evaluated as inhibitors of E. coli EPSP synthase. These simple, synthetically accessible aromatic analogues are highly effective competitive inhibitors versus S3P with an apparent Ki for the tetrahedral intermediate analogue 4 of 160 +/- 40 nM. This demonstrates that a simple benzene ring is a quite suitable substitute for the complex shikimate ring in the design of EPSP synthase inhibitors.
Miller
M J
MJ
Life Sciences Research Center, Monsanto Company, St. Louis, Missouri 63198.
Ream
J E
JE
Walker
M C
MC
Sikorski
J A
JA
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D019883:Alkyl and Aryl Transferases; D001667:Binding, Competitive; D004926:Escherichia coli / Q000201:enzymology; D062385:Hydroxybenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012118:Resorcinols; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*
D062385:Hydroxybenzoates; D012118:Resorcinols; C076950:alpha-resorcylic acid; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase