Theoretical study of gas-phase acidity, pKa, lipophilicity, and solubility of some biologically active sulfonamides

The geometries of 19 biologically active substituted sulfonamides (including clinically useful acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) in both neutral and deprotonated forms, were optimized using Becke3LYP/6-311+G(d,p) method (compounds 1-6) and two-layered ONIOM (B3LYP 6-311+G(d,p): MNDO) method (compounds 7-19). The investigated sulfonamides are weak acids with calculated acidity of about 1320-1420kJ mol(-1). Of acids studied the highest gas-phase acidity (1324kJ mol(-1)) possesses methazolamide. This drug is, according to the computed pK(a) value (5.9), also in water solution the most acidic compound of the sulfonamides investigated. The computed pK(a) values varied between 5.9 and 12.6 and correlate well with the available experimental pK(a)'s found in the literature. Cancerostatic aromatic sulfonamides 16-19 are generally weak acids with the acidity comparable or slightly lower than the lead sulfanilamide. The available experimental partition coefficients of sulfonamides investigated are best reproduced by the IA LOGP method. Computed partition coefficients for antiglaucoma sulfonamides 1-13 varied between -0.47 and 2.61 (IA LOGP). Thus these compounds are only slightly or moderate lipophilic. The lipophilicity of the cancerostatic sulfonamides 14-18 is from relatively narrow interval between -0.07 and 1.68 (IA LOGP). The most potent CAI 10-13 are also the most lipophilic compounds among the antiglaucomatics studied. The available experimental solubilities are best reproduced by the IA LOGS method. The computed solubilities qualitatively correlate with the corresponding lipophilicities, logS increasing as logP declines. The analysis of molecular descriptors defined by Lipinski have been shown that all of the sulfonamides studied obey 'Rule of 5'. Therefore, in the early stages of the design of antiglaucoma sulfonamides, it is becoming more important to determine the pK(a) lipophilicity, water solubility, and other physicochemical properties associated with a drug, before synthetic work is undertaken, with the aim of avoiding the synthesis of compounds that are predicted to have poor biopharmaceutical characteristics. (C) 2004 Elsevier Ltd. All rights reserved.