Design, synthesis and inhibition activity of a novel cyclic enediyne amino acid conjugates against MPtpA

Bioorg Med Chem. 2011 May 15;19(10):3274-9. doi: 10.1016/j.bmc.2011.03.024. Epub 2011 Mar 30.

Abstract

In course of studies towards the discovery of selective inhibitors of MPtpA, a novel cyclic endiyne malonamic acid has been designed and synthesized. The synthesis involves a crucial intramolecular Knoevenagel reaction. The compound displayed a reversible non-competitive inhibition against MPtpA with inhibition constant K(i) of 22.5 μM. The enediyne acts as a recognition framework in inducing the inhibition and not as a reactive functional moiety. This was confirmed by comparing the inhibiting activity with that of the corresponding saturated cyclic non-enediyne analogue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Cyclic / chemical synthesis
  • Amino Acids, Cyclic / chemistry
  • Amino Acids, Cyclic / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Cyclization
  • Drug Design
  • Enediynes / chemical synthesis
  • Enediynes / chemistry*
  • Enediynes / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Malonates / chemical synthesis
  • Malonates / chemistry
  • Malonates / pharmacology
  • Models, Molecular
  • Mycobacterium tuberculosis / enzymology*
  • Protein Binding
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / metabolism
  • Tuberculosis / drug therapy

Substances

  • Amino Acids, Cyclic
  • Bacterial Proteins
  • Enediynes
  • Enzyme Inhibitors
  • Malonates
  • MptpA protein, Mycobacterium tuberculosis
  • malonamic acid
  • Protein Tyrosine Phosphatases