4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki-Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies

J Med Chem. 2016 Jan 28;59(2):721-32. doi: 10.1021/acs.jmedchem.5b01771. Epub 2016 Jan 15.


Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para-position were prepared by palladium nanoparticle-catalyzed Suzuki-Miyaura cross-coupling reactions and evaluated as human carbonic anhydrase (hCA, EC inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl-aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Catalysis
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / pharmacology
  • Models, Molecular
  • Nanostructures
  • Neoplasms / enzymology
  • Palladium / chemistry*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology*


  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Palladium