Bioorganic & Medicinal Chemistry Letters 2008-06-15

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

Alessio Innocenti, Mika Hilvo, Andrea Scozzafava, Seppo Parkkila, Claudiu T Supuran

Index: Bioorg. Med. Chem. Lett. 18 , 3593-6, (2008)

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Abstract

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 microM, whereas compounds incorporating 4-amino-, 4-cyano, or 3-hydroxy groups were less effective (K(I)s of 335-434 microM). The best phenol inhibitor was clioquinol (K(I) of 2.33 microM). 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.