Carbonic anhydrase inhibitors - Part 49: Synthesis of substituted ureido and thioureido derivatives of aromatic/heterocyclic sulfonamides with increased affinities for isozyme I

Abstract

Reaction of nine aromatic/heterocyclic sulfonamides containing a free amino group with aryl isocyanates/isothiocyanates or allyl isothiocyanate afforded the corresponding urea/thiourea derivatives, which were characterized by standard physico-chemical procedures and assayed as inhibitors of three isozymes of carbonic anhydrase (CA), i.e. hCA I, hCA II and bCA IV (h = human, b = bovine isozyme). Another series of compounds, 1,5-disubstituted-2-thiobiuret derivatives, were prepared by reaction of 3,4-dichlorophenyl isocyanate with thioureido-containing aromatic/heterocyclic sulfonamides. Good inhibition of all these three CA isozymes was observed with the new compounds, but an exciting finding was that the ureas/thioureas and especially the above-mentioned thiobiurets reported here have an increased affinity to the slow isozyme hCA I, generally less susceptible to inhibition by sulfonamides, as compared to the rapid isozymes hCA II and bCA IV. Some of the new compounds might constitute good lead molecules for developing more selective CA I inhibitors.