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 profile 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 µM, whereas compounds incorporating 4-amino-, 4-cyano, or 3-hydroxy groups were less effective (KIs of 335–434 µM). The best phenol inhibitor was clioquinol (KI of 2.33 µM). 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.