Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action

Bioorg Med Chem. 2016 Feb 15;24(4):894-901. doi: 10.1016/j.bmc.2016.01.012. Epub 2016 Jan 8.

Abstract

A set of N,N'-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with Ki values in the low nanomolar-subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the Ki values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallography.

Keywords: Carbonic anhydrase; Docking; Epilepsy; Sodium cyclamate; Sulfamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Binding Sites
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrases / chemistry*
  • Cyclamates / chemistry
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Secondary
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry

Substances

  • Anticonvulsants
  • Carbonic Anhydrase Inhibitors
  • Cyclamates
  • Isoenzymes
  • Sulfonamides
  • Carbonic Anhydrases
  • carbonic anhydrase VI