5-Substituted-(1,2,3-triazol-4-yl)thiophene-2-sulfonamides strongly inhibit human carbonic anhydrases I, II, IX and XII: solution and X-ray crystallographic studies

Bioorg Med Chem. 2013 Sep 1;21(17):5130-8. doi: 10.1016/j.bmc.2013.06.041. Epub 2013 Jun 27.


We report here a series of 2-thiophene-sulfonamides incorporating 1-substituted aryl-1,2,3-triazolyl moieties, prepared by click chemistry from 5-ethynylthiophene-2-sulfonamide and substituted aryl azides. The new sulfonamides were investigated as inhibitors of the zinc metalloenzyme CA (EC, and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated ones hCA IX and XII: The new compounds were medium-weak hCA I inhibitors (KIs in the range of 224-7544nM), but were compactly, highly effective, low nanomolar hCA II inhibitors (KIs of 2.2-7.7nM). The tumor-associated hCA IX was inhibited with KIs ranging between 5.4 and 811nM, whereas hCA XII with inhibition constants in the range of 3.4-239nM. The X-ray crystal structure of the adducts of two such compounds bound to hCA II (one incorporating 1-naphthyl, the other one 3-cyanophenyl moieties) evidenced the reasons of the high affinity for hCA II. Highly favorable, predominantly hydrophobic interactions between the sulfonamide scaffold and the hCA II active site were responsible for the binding, in addition to the coordination of the sulfamoyl moiety to the zinc ion. The tails of the two inhibitors adopted very diverse orientations when bound to the active site, with the naphthyltriazolyl moiety orientated towards the hydrophobic half of the active site, and the 3-cyanophenyl one pointing towards the hydrophilic half. These data may be used for the structure-based drug design of even more effective hCA II inhibitors, with potential use as antiglaucoma agents or as diuretics.

Keywords: Carbonic anhydrase; Click chemistry; Enzyme inhibitor; Sulfonamide; Thiophene-2-sulfonamide; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / metabolism
  • Binding Sites
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrases / chemistry*
  • Carbonic Anhydrases / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / metabolism


  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Sulfonamides
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII