A DFT-Based QSARs Study of Acetazolamide/Sulfanilamide Derivatives with Carbonic Anhydrase (CA-II) Isozyme Inhibitory Activity

This study presents Quantitative Structure Activity Relationships (QSAR) studyon a pool of 18 bio-active sulfonamide compounds which includes five acetazolamidederivatives, eight sulfanilamide derivatives and five clinically used sulfonamides moleculesas drugs namely acetazolamide, methazolamide, dichlorophenamide, ethoxolamide anddorzolamide. For all the compounds, initial geometry optimizations were carried out with amolecular mechanics (MM) method using the MM force fields. The lowest energyconformations of the compounds obtained by the MM method were further optimized by theDensity Functional Theory (DFT) method by employing Becke’s three-parameter hybridfunctional (B3LYP) and 6-31G (d) basis set. Molecular descriptors, dipole moment,electronegativity, total energy at 0 K, entropy at 298 K, HOMO and LUMO energiesobtained from DFT calculations provide valuable information and have a significant role inthe assessment of carbonic anhydrase (CA-II) inhibitory activity of the compounds. By usingthe multiple linear regression technique several QSAR models have been drown up with thehelp these calculated descriptors and carbonic anhydrase (CA-II) inhibitory data of themolecules. Among the obtained QSAR models presented in the study, statistically the mostsignificant one is a five parameters linear equation with the squared correlation coefficient R2 values of ca. 0.94 and the squared cross-validated correlation coefficient R2CV values of ca. 0.85. The results were discussed in the light of the main factors that influence theinhibitory activity of the carbonic anhydrase (CA-II) isozyme