Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases

J Med Chem. 2005 Apr 21;48(8):2906-15. doi: 10.1021/jm049011j.


Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2) > 0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Animals
  • Butyrylcholinesterase / chemistry
  • Carboxylesterase / antagonists & inhibitors*
  • Carboxylic Ester Hydrolases / antagonists & inhibitors
  • Carboxylic Ester Hydrolases / chemistry
  • Cholinesterase Inhibitors / chemistry
  • Databases, Factual
  • Humans
  • Intestines / enzymology
  • Models, Molecular
  • Phenylglyoxal / analogs & derivatives*
  • Phenylglyoxal / chemical synthesis
  • Phenylglyoxal / chemistry*
  • Quantitative Structure-Activity Relationship
  • Rats
  • Structure-Activity Relationship
  • Umbelliferones / chemistry


  • Cholinesterase Inhibitors
  • Umbelliferones
  • 4-methylumbelliferyl acetate
  • Carboxylic Ester Hydrolases
  • CES1 protein, human
  • Carboxylesterase
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Phenylglyoxal
  • benzil