Carbonic anhydrase inhibitors - Part 53. Synthesis of substituted-pyridinium derivatives of aromatic sulfonamides: The first non-polymeric membrane-impermeable inhibitors with selectivity for isozyme IV

Reaction of three aromatic sulfonamides containing a free amino group, i.e., sulfanilamide, homosulfanilamide and 4-(2-aminoethyl)-benzenesulfonamide with di-, tri- or tetra-substituted pyrylium salts afforded three series of cationic sulfonamides, containing a large variety of moieties substituting the pyridinium ring. The new derivatives were assayed as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but due to the cationic nature of these inhibitors, in vivo and ex vivo experiments showed that only CA IV is selectively inhibited to a high degree, without affecting the cytosolic isozymes, present in appreciable concentrations in the experimental model used. This is the first example of selective in vivo inhibition of only one physiologically relevant CA isozyme with non-polymeric inhibitors and might lead to more selective drugs from this class of pharmacological agents.