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 μM against CA I, of 0.090–870 μM against CA II, of 0.71–885 μM against CA III, of 9.5–809 μM against CA IV, of 8.7–867 μM against CA VA, of 4.2–649 μM against CA VB, of 11.4–658 μM against CA VI, of 9.1–1359 μM against CA VII, of 8.8–517 μM against CA IX, of 4.1–598 μM against CA XII, of 12.2–697 μM against CA XIII and of 10.1–49.8 μM against CA XIV, respectively. The different mechanisms of inhibition by phenols as compared to sulfonamides, and their diverse inhibition profile 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.

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