Carbonic anhydrase inhibitors: Synthesis of sulfonamides incorporating 2,4,6-trisubstituted-pyridinium-ethylcarboxamido moieties possessing membrane-impermeability and in vivo selectivity for the membrane-bound (CA IV) versus the cytosolic (CA I and CA II) isozymes

A new approach is proposed for the selective in vivo inhibition of membrane -bound versus cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes with a class of positively-charged, membrane-impermeant sulfonamides. Aromatic/he terocyclic sulfonamides acting as strong (but unselective) inhibitors of th is zinc enzyme were derivatized by the attachment of trisubstituted-pyridin ium-ethylcarboxy moieties (obtained from 2,4,6-trisubstituted-pyrylium salt s and beta-alanine) to the amino, imino, hydrazino or hydroxyl groups prese nt in their molecules. Efficient in vitro inhibition tin the nanomolar rang e) was observed with some of the new derivatives against three investigated CA isozymes, i.e., hCA I, hCA II (cytosolic forms) and bCA IV (membrane-bo und isozyme; h = human; b = bovine isozyme). Due to their salt-like charact er, the new type of inhibitors reported here, unlike the classical, clinica lly used compounds (such as acetazolamide, methazolamide, ethoxzolamide), a re unable to penetrate biological membranes.