A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides. Sulfonamide Carbonic Anhydrase Inhibitors: Quantum Chemical QSAR

Molecular orbital (MO) indices were computed (CNDO/2) for a wide series of heterocyclic (thiadiazole, thiazole, and thiophene) sulfonamide inhibitors of the zinc-enzyme carbonic anhydrase. Linear regression analyses between the calculated indices and enzyme inhibition data provide good correlations which enable us to generalize the electronic structure-inhibitory activity relationships in heteroaromatic and aromatic sulfonamide inhibitors. In particular. a) the less electron-rich the sulfamoyl group is, the more favoured are both the hydrophobic and hydrophilic steps leading to enzyme inhibition. b) the combined effects of the hydrophobicity of the common part of the heterocyclic rings and the hydrophilicity of the ring nitrogen atoms are probably the factors mainly responsible for the enhanced activity by a factor of 17.4 of heteroaromatic sulfonamides with respect to the aromatic one.