menaquinone-6 and sulfamic-acid

N-Acyl sulfamoyladenosines (acyl-AMS) have been used extensively to inhibit adenylate-forming enzymes that are involved in a wide range of biological processes. These acyl-AMS inhibitors are nonhydrolyzable mimics of the cognate acyl adenylate intermediates that are bound tightly by adenylate-forming enzymes. However, the anionic acyl sulfamate moiety presents a pharmacological liability that may be detrimental to cell permeability and pharmacokinetic profiles. We have previously developed the acyl sulfamate OSB-AMS (1) as a potent inhibitor of the adenylate-forming enzyme MenE, an o-succinylbenzoate-CoA (OSB-CoA) synthetase that is required for bacterial menaquinone biosynthesis. Herein, we report the use of computational docking to develop novel, non-acyl sulfamate inhibitors of MenE. A m-phenyl ether-linked analogue (5) was found to be the most potent inhibitor (IC

Topics: Crystallography, X-Ray; Drug Design; Enzyme Inhibitors; Escherichia coli; Escherichia coli Proteins; Kinetics; Microbial Sensitivity Tests; Models, Chemical; Molecular Docking Simulation; Molecular Structure; Mutation; Protein Conformation; Succinate-CoA Ligases; Sulfonic Acids; Vitamin K 2