Carbonic anhydrase inhibitors: Thioxolone versus sulfonamides for obtaining isozyme-selective inhibitors?

Inhibition of 13 mammalian isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA I-XV, with thioxolone (6-hydroxy-1,3-benzoxathiol-2-one) and two sulfonamides was investigated. Thioxolone was inefficient for generating isozyme-selective inhibitors, since except for CA I which is inhibited in the nanomolar range (K(I) of 91 nM), the remaining 12 isoforms were inhibited with a very. at pro. le (K(I)s in the range of only 4.93-9.04 mu M). In contrast to thioxolone, 3,5-dichloro-4-hydroxybenzenesulf-onamide as well as the clinically used heterocyclic sulfonamide acetazolamide showed KIs in the range of 58 nM-78.6 mu M and 2.5 nM-200 mu M, respectively, against the 13 investigated mammalian CAs. The sulfonamide zinc-binding group is thus superior to the thiol one for generating CA inhibitors with a varied and sometimes isozyme-selective inhibition pro. le against the mammalian enzymes. (C) 2008 Elsevier Ltd. All rights reserved.