Design, synthesis and X-ray crystallography of selenides bearing benzenesulfonamide moiety with neuropathic pain modulating effects

Eur J Med Chem. 2018 Jun 25:154:210-219. doi: 10.1016/j.ejmech.2018.05.026. Epub 2018 May 19.

Abstract

A series of selenides bearing benzensulfonamide were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Potent inhibitory action, in the low nanomolar range, was detected against isoforms hCA II and VII, which are known to be involved in neuropathic pain modulation. These selenides showed on the other hand moderate inhibition against the cytosolic isoforms hCA I and transmembrane hCA IX. X-ray crystallographic data of two derivatives bound to hCA II allowed us to rationalize the excellent inhibitory data. In a mice model of neuropathic pain induced by oxaliplatin, some of the strong CA II/VII inhibitors induced a long lasting pain relieving effect.

Keywords: Carbonic Anhydrase Inhibitors (CAIs); Metalloenzymes; Neuropathic pain; Organoselenium; Selenium.

MeSH terms

  • Animals
  • Benzenesulfonamides
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neuralgia / chemically induced
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Organoplatinum Compounds
  • Oxaliplatin
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Organoplatinum Compounds
  • Sulfonamides
  • Oxaliplatin
  • Carbonic Anhydrases