Discovery of 1,1'-Biphenyl-4-sulfonamides as a New Class of Potent and Selective Carbonic Anhydrase XIV Inhibitors

J Med Chem. 2015 Nov 12;58(21):8564-72. doi: 10.1021/acs.jmedchem.5b01144. Epub 2015 Nov 4.


New 1,1'-biphenylsulfonamides were synthesized and evaluated as inhibitors of the ubiquitous human carbonic anhydrase isoforms I, II, IX, XII, and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides 1-21 inhibited all the isoforms, with Ki values in the nanomolar range of concentration, and were superior to AAZ against all of them. X-ray crystallography and molecular modeling studies on the adducts that compound 20, the most potent hCA XIV inhibitor of the series (Ki = 0.26 nM), formed with the five hCAs, provided insight into the molecular determinants responsible for the high affinity of this molecule toward the target enzymes. The results pave the way to the development of 1.1'-biphenylsulfonamides as a new class of highy potent hCA XIV inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / pharmacology*
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*


  • Biphenyl Compounds
  • Carbonic Anhydrase Inhibitors
  • Sulfonamides
  • diphenyl
  • Carbonic Anhydrases
  • carbonic anhydrase XIV