Carbonic anhydrase inhibitors: Inhibition of the new membrane-associated isoform XV with phenols

Inhibition of the newest isoform of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA XV, with a series of phenols was investigated. Murine CA XV showed an inhibition pro. le by phenols distinct of those of the cytosolic human isoforms CA I and II. Phenol and some of its 2-,3-, and 4-substituted derivatives incorporating hydroxy, fluoro, carboxy, and acetamido moieties were effective CA XV inhibitors, with inhibition constants in the range of 7.20-11.30 mu M, whereas compounds incorporating 4-amino-, 4-cyano, or 3-hydroxy groups were less effective (K(1)s of 335-434 mu M). The best phenol inhibitor was clioquinol (K(1) of 2.33 mu M). Phenols show a different inhibition mechanism as compared to sulfonamides and their isosteres, and may lead to the design of compounds with selectivity for inhibiting different CA isozymes with medicinal chemistry applications. (C) 2008 Elsevier Ltd. All rights reserved.