Enediol mimics as inhibitors of the d-arabinose 5-phosphate isomerase (KdsD) from Francisella tularensis

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 9; pp. 2679 - 2682
• Main Authors: Yep, Alejandra, Sorenson, Roderick J., Wilson, Michael R., Hollis Showalter, H.D., Larsen, Scott D., Keller, Paul R., Woodard, Ronald W.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.05.2011; Elsevier
• Subjects: Alcohols - chemical synthesis; Alcohols - chemistry; Alcohols - pharmacology; Aldose-Ketose Isomerases - antagonists & inhibitors; Aldose-Ketose Isomerases - genetics; Aldose-Ketose Isomerases - metabolism; Alkenes - chemical synthesis; Alkenes - chemistry; Alkenes - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; d-Arabinose 5-phosphate isomerase (A5PI); Drug Design; Enediol; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli - genetics; Francisella tularensis; Francisella tularensis - drug effects; Francisella tularensis - enzymology; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Inhibitor design; Inhibitory Concentration 50; KdsD (EC 5.3.1.13); Medical sciences; Molecular Structure; pathogens; Pharmacology. Drug treatments; synthetic genes; d-Arabinose 5-phosphate isomerase (A5PI); Inhibitor design; KdsD (EC 5.3.1.13); Francisella tularensis; Enediol; Intramolecular oxidoreductases; Enzyme; Hydroxamic acid; Enzyme inhibitor; In vitro; Phosphorus Organic compounds; D-Arabinose 5-phosphate isomerase (A5PI); Arabinose-5-phosphate isomerase; Isomerases; Structure activity relation; Organic phosphate; Bacteria; Antibacterial agent; Chemical synthesis; Acylate
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.066

We explored the d-arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Francisella tularensis, a highly infectious Gram-negative pathogen that has raised concern as a potential bioweapon, as a target for the development of novel chemotherapeutics. F. tularensis KdsD was expressed in Escherichia coli from a synthetic gene, purified, and characterized. A group of hydroxamates designed to be mimics of the putative enediol intermediate in the enzyme’s catalytic mechanism were prepared and tested as inhibitors of F. tularensis KdsD. The best inhibitor, which has an IC 50 of 7 μM, is the most potent KdsD inhibitor reported to date.