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 (K(I)s of 2.7-11.5 mu M) and a less effective one against the other isoforms, CA VA, VB, VI, VII, and XIII (K(I)s of 208-710 mu M). 3,5-Difluorophenol was an effective inhibitor of CA III, IV, IX, and XIV (K(I)s of 0.71-10.7 mu M) being a weaker one for CA I, II, VA, VB, VI, VII, XII, and XIII (K(I)s of 33.9-163 mu M). 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 mu M. 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. (c) 2008 Elsevier Ltd. All rights reserved.