Synthesis of sulfonamide-containing N-hydroxyindole-2-carboxylates as inhibitors of human lactate dehydrogenase-isoform 5

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7331-6. doi: 10.1016/j.bmcl.2011.10.031. Epub 2011 Oct 17.

Abstract

N-Hydroxyindole-2-carboxylates possessing sulfonamide-substituents at either position 5 or 6 were designed and synthesized. The inhibitory activities of these compounds against isoforms 1 and 5 of human lactate dehydrogenase were analysed, and K(i) values of the most efficient inhibitors were determined by standard enzyme kinetic studies. Some of these compounds displayed state-of-the-art inhibitory potencies against isoform 5 (K(i) values as low as 5.6 μM) and behaved as competitive inhibitors versus both the substrate and the cofactor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Computer Simulation
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indoles / chemistry*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Kinetics
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / metabolism
  • Lactate Dehydrogenase 5
  • Protein Structure, Tertiary
  • Sulfonamides / chemistry*

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Indoles
  • Isoenzymes
  • Sulfonamides
  • indole
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • lactate dehydrogenase 1