Carbonic anhydrase inhibitors: Interactions of phenols with the 12 catalytically active mammalian isoforms (CA I–XIV)

The inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with three phenols was investigated. Phenol was an effective CA I–IV, IX, XII and XIV inhibitor (KIs of 2.7–11.5 μM) and a less effective one against the other isoforms, CA VA, VB, VI, VII, and XIII (KIs of 208–710 μM). 3,5-Difluorophenol was an effective inhibitor of CA III, IV, IX, and XIV (KIs of 0.71–10.7 μM) being a weaker one for CA I, II, VA, VB, VI, VII, XII, and XIII (KIs of 33.9–163 μM). Clioquinol (5-chloro-7-iodo-8-quinolinol) was the best phenol inhibitor against all isozymes, with inhibition constants in the range of 3.3–16.0 μM. These data prove that the phenol OH moiety can be considered as a new ‘zinc–water binding group’ for the design of CA inhibitors possessing a different inhibition mechanism as compared to the classical sulfonamide inhibitors that bind the metal ion within the active site cavity.