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

Abstract

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 1320–1420 kJ mol⁻¹. Of acids studied the highest gas-phase acidity (1324 kJ 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, log S increasing as log P 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.

Introduction

The sulfonamide –SO₂NH– group occurs in numerous biologically active compounds, which include antimicrobial drugs, saluretics, carbonic anhydrase inhibitors, insulin-releasing sulfonamides, antithyroid agents antitumor drugs, and number of other biological activities.[1], [2], [3] Many sulfonamides with the general formula R–SO₂NH₂ constitute an important class of inhibitors of the zinc enzyme carbonic anhydrase⁴ (CA) due to their use in antiglaucoma therapy.[5], [6], [7], [8] They bind as anions to the Zn²⁺ ion within the enzyme active site[9], [10], [11] (with abnormally high affinities of around 10⁶–10⁹ M⁻¹ for isozyme CA II, Refs. [12], [13], [14]). Sulfonamides are weak organic acids.¹⁵ Because medicinally useful antiglaucoma drugs are aromatic sulfonamides, it is evident that for optimal in vivo activity the balanced hydro- and liposolubility is necessary. Simple aliphatic sulfonamides exhibit good water solubility.¹⁵ Aromatic sulfonamides possessing large hydrophobic domains are generally substantially less soluble.¹⁵ It is well established[16], [17] that a water-soluble sulfonamide, also possessing a relatively balanced lipid solubility, would be an effective antiglaucoma drug via the topical route. One of the conditions¹⁶ needed for a sulfonamide to act as an effective intraocular pressure lowering agent is to possess a modest lipid solubility (attributable to its unionized form). 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.

The physicochemical characteristics of some of the prepared antiglaucoma sulfonamides were experimentally determined.⁴ Unfortunately, not much is known about the theoretical determination of molecular structure, ionization, and complexation with metal ions of medicinally useful sulfonamides. Murcko¹⁸ carried out conformational analysis of methane sulfonamide anion using ab initio methods. In a recent work¹⁵ large-scale theoretical quantum chemical methods were used to determine stable conformations, gas-phase acidity, lipophilicity, and hydrophilicity of 11 aliphatic and aromatic sulfonamides for which a relatively small amount of experimental physicochemical data exist, considering their pharmacological importance. Thermodynamics of binding of Zn(II) to carbonic anhydrase inhibitors was also investigated.¹⁹ Computational chemistry was also used for screening of novel inhibitors of human carbonic anhydrase.[20], [21], [22] Klebe and co-workers[20], [21] used several methods for virtual screening of compound libraries. On the basis of predicted affinity 13 new compounds was prepared and experimentally tested. Of these 13, four compounds were shown to be nanomolar or subnanomolar inhibitors.²¹ Shakhnovich and co-workers²² used combinatorial computational method for prediction of new ligands for hCA II. One of the designed ligands is the best-known inhibitor²² with experimentally verified binding affinity K_d ≈ 30 pM.

In this paper we have used theoretical methods for the study of stable geometries of 19 biologically active aromatic and heteroaromatic sulfonamides in both neutral and anionic forms. All structures of these most representative sulfonamides investigated are shown in Figure 1. Of particular interest are the molecular geometries, gas-phase acidities, pK_a, solubilities, and lipophilicities of the species. The results of theoretical studies of sulfonamides were compared with the available experimental data and discussed with the present theories of action of these inhibitors of carbonic anhydrase.