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

Alessio Innocenti, Alfonso Maresca, Andrea Scozzafava, Claudiu T. Supuran, Alessio Innocenti, Alfonso Maresca, Andrea Scozzafava, Claudiu T. Supuran

Index: Bioorg. Med. Chem. Lett. 18(14) , 3938-41, (2008)

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Abstract

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 flat profile (K(I)s in the range of only 4.93-9.04 microM). In contrast to thioxolone, 3,5-dichloro-4-hydroxybenzenesulfonamide as well as the clinically used heterocyclic sulfonamide acetazolamide showed K(I)s in the range of 58 nM-78.6 microM and 2.5 nM-200 microM, 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 profile against the mammalian enzymes.