Abstract
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.
Highlights
Acetazolamide, methazolamide, dichlorophenamide, ethoxolamide and dorzolamide, as carbonic anhydrase (CA-II) isozyme inhibitors, sulfonamide compounds are clinically used drugs for the treatment of glaucoma [1]
CA-II reversibly catalyzes the reaction of H2O and CO2 to form carbonic acid and subsequently the bicarbonate ion
The leading cause of blindness worldwide, is the general term for a group of ophthalmic disorders characterized by an increase in intraocular pressure (IOP)
Summary
Acetazolamide, methazolamide, dichlorophenamide, ethoxolamide and dorzolamide, as carbonic anhydrase (CA-II) isozyme inhibitors, sulfonamide compounds are clinically used drugs for the treatment of glaucoma [1]. Modification of the structure of a known drug is one way to develop new drugs For this purpose, members of our group have synthesized and reported new five acetazolamide-like and eight sulfanilamide-like derivatives, which are the subject of the present study. The inhibition constants (KI) of these new molecules against the carbonic anhydrase enzyme CA II are shown, are much lower than their mother molecule acetazolamide and sulfanilamide These derivatives can be the subject of further investigation to explore the possibilities of becoming candidate drugs. Aim of the present study is to build QSAR models using multiple regression method, to explore the correlations between the experimental the inhibition constants (KI) and calculated molecular descriptors of 18 aromatic and heterocyclic sulfonamide compounds
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