Molecular structure, pKa, lipophilicity, solubility and absorption of biologically active aromatic and heterocyclic sulfonamides

The methods of theoretical chemistry have been used to elucidate molecular properties of clinically useful acetazolamide, dorzolamide and brinzolamide and two new aromatic sulfonamides in both neutral and deprotonated forms. The geometries and energies of these drugs have been computed using HF/6-31G(d), Becke3LYP/6-31G(d) and Becke3LYP/6-311+G(d,p) model chemistries. The equilibrium structure of the acetazolamide is stabilized via intramolecular interaction between non-bonded S center dot center dot center dot O atoms of the acetylamino group and the thiadiazole ring. in the case of the aromatic sulfonamides (4-sulfamoyl-N-(3-morpholinopropyl) benzamide (P20), and N-(morpholinopropyl)benzene-1,4-bis(sulfonamide) (P20)) the fully optimized most stable conformers possess characteristic L-shape structure stabilized via intramolecular hydrogen bonding system of the N-H center dot center dot center dot N type. Computed partition coefficients (XLOGP2 method) for drugs studied varied between -0.3 and -1.8. Neutral compounds are described as slightly lipophilic drugs. The calculated water solubility of dorzolamide and brinzolamide is comparably low. P10 and P20 are slightly lipophilic sulfonamides with moderate Solubility. The calculated pK(a) values of -SO2NH2 moiety in the sulfonamides studied are in the range of 7.3-9.7 and are characterized as weak organic acids. (C) 2009 Elsevier B.V. All rights reserved.