Inhibition Studies on Carbonic Anhydrase Isoforms I, II, IX, and XII with a Series of Sulfaguanidines

Two novel sulfaguanidine series, six N-(N,N'-dialkyl/dibenzyl-carbamimidoyl) benzenesulfonamide derivatives and nine N-(N-alkyl/benzyl-carbamimidoyl) benzenesulfonamide derivatives, were obtained by desulfidative amination of easily accessible dimethyl arylsulfonylcarbonimidodithioates under catalyst- and base-free conditions. The newly synthesized compounds were tested for the inhibition of four different isozymes of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). Both series reported here were inactive against the off-target isozymes hCA I and II (Ki >100 μM). Interestingly, all investigated compounds inhibited both target isozymes hCA IX and XII in the submicromolar to micromolar ranges in which Ki values spanned from 0.168 to 0.921 μM against hCA IX and from 0.335 to 1.451 μM against hCA XII. The results indicated that N-(N-alkyl/benzyl-carbamimidoyl) benzenesulfonamides were slightly more potent inhibitors than N-(N,N'-dialkyl/dibenzyl-carbamimidoyl) benzenesulfonamides. Among the evaluated compounds, N-n-octyl-substituted N-carbamimidoylbenzenesulfonamide showed the most significant activity with a Ki value of 0.168 μM against hCA IX, which was four-fold more selective toward this isozyme versus hCA XII. Again, another derivative from N-(N-alkyl/benzyl-carbamimidoyl) benzenesulfonamide series, N-p-methylbenzyl-substituted N-carbamimidoylbenzenesulfonamide, demonstrated superior inhibitory activity against hCA XII with a Ki value of 0.335 μM.