Carbonic anhydrase inhibitors: Inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid

Inhibition of 12 mammalian isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA I-XIV, with a series of phenols was investigated. The inhibition profile by phenols of these CAs was distinct from those of the sulfonamides and their isosteres, the main class of clinically used inhibitors. Phenol and some of its 2-, 3-and 4-substituted derivatives incorporating hydroxy-,fluoro-, carboxy-, amino-, cyano- and acetamido-moieties were generally effective low micromolar CA inhibitors, with inhibition constants in the range of 9.8-4003 mu M against CA I, of 0.090-870 mu M against CA II, of 0.71-885 mu M against CA III, of 9.5-809 mu M against CA IV, of 8.7-867 mu M against CA VA, of 4.2-649 mu M against CA VB, of 11.4-658 mu M against CA VI, of 9.1-1359 mu M against CA VII, of 8.8-517 mu M against CA IX, of 4.1-598 mu M against CA XII, of 12.2-697 mu M against CA XIII and of 10.1-49.8 mu M against CA XIV, respectively. The different mechanisms of inhibition by phenols as compared to sulfonamides, and their diverse inhibition pro. le for these mammalian isozymes, makes this class of derivatives of great interest for the design of compounds with selectivity and/or specificity for some of the medicinal chemistry targets belonging to this enzyme family. (C) 2008 Elsevier Ltd. All rights reserved.