Kinetic and X-ray crystallographic investigations of substituted 2-thio-6-oxo-1,6-dihydropyrimidine-benzenesulfonamides acting as carbonic anhydrase inhibitors

Bioorg Med Chem. 2016 Aug 15;24(16):3643-8. doi: 10.1016/j.bmc.2016.06.005. Epub 2016 Jun 4.

Abstract

Herein we report an in vitro kinetic evaluation against the most relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms (I, II, IX and XII) of a small series of lactate dehydrogenase (LDH, EC 1.1.1.27) inhibitors. All compounds contain a primary sulfonamide zinc-binding group (ZBG) substituted with the 2-thio-6-oxo-1,6-dihydropyrimidine scaffold. By means of X-ray crystallographic experiments we explored the ligand-enzyme binding modes, thus highlighting the contribution of the 2-thio-6-oxo-1,6-dihydropyrimidine moiety to the stabilization of the complex.

Keywords: 2-Thio-6-oxo-1,6-dihydropyrimidines; Carbonic anhydrase (CA); Sulfonamides; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / chemistry
  • Crystallography, X-Ray
  • Isoenzymes / chemistry
  • Kinetics
  • Molecular Structure
  • Sequence Homology, Amino Acid
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Carbonic Anhydrases