Functionalized 3,5-dihydroxybenzoates as potent novel inhibitors of EPSP synthase

• Published in: Bioorganic & medicinal chemistry 1994-05, Vol.2 (5), p.331-338
• Main Authors: Miller, Michael J., Ream, Joel E., Walker, Mark C., Sikorski, James A.
• Format: Article
• Language: English
• Subjects: 3-Phosphoshikimate 1-Carboxyvinyltransferase; Alkyl and Aryl Transferases; Binding, Competitive; Escherichia coli - enzymology; Hydroxybenzoates - chemical synthesis; Hydroxybenzoates - chemistry; Hydroxybenzoates - pharmacology; In Vitro Techniques; Kinetics; Magnetic Resonance Spectroscopy; Molecular Structure; Resorcinols; Structure-Activity Relationship; Transferases - antagonists & inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)82189-6

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 KK i 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. Aromatic analogues of the EPSP synthase reaction substrate, product and tetrahedral intermediate were synthesized from 3,5-dihyroxybenzoic acid. These readily accessible analogues are highly effective competitive inhibitors (vs. S3P) of E. Coli EPSP synthase indicating that a benzene ring is a very effective substitute for the complex shikimate in EPSP synthase inhibitors.