Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies

Bioorg Med Chem. 2014 Aug 1;22(15):3982-8. doi: 10.1016/j.bmc.2014.06.003. Epub 2014 Jun 26.

Abstract

Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s>10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K(i) value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII.

Keywords: Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / metabolism
  • Binding Sites
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrases / chemistry*
  • Carbonic Anhydrases / metabolism
  • Catalytic Domain
  • Humans
  • Molecular Docking Simulation
  • Probenecid / chemistry*
  • Protein Binding
  • Structure-Activity Relationship
  • Sulfonamides / chemistry

Substances

  • Amides
  • Carbonic Anhydrase Inhibitors
  • Sulfonamides
  • Carbonic Anhydrase II
  • CA13 protein, human
  • Carbonic Anhydrases
  • Probenecid