Development of New Aromatic Sulfonamides as Potential Antiglaucoma Agents

Many sulfonamides with the general formula R-SO₂NH₂ constitute an important class of inhibitors of the zinc enzyme carbonic anhydrase (CA) due to their use in antiglaucoma therapy. It is well established that a water-soluble sulfonamide, also possessing relatively balanced lipid solubility, would be an effective antiglaucoma drug via the topical route.

Design of new aromatic sulfonamides was carried out using computational methods of theoretical medicinal chemistry as described in our previous works.  Of particular interest are the molecular geometries of neutral and anionic species, acidities, and lipophilicities. Synthesis of the so-designed new aromatic sulfonamides was conducted according to published procedures. Antiglaucoma activity was evaluated in both in vitro and in vivo conditions. For determination of the intraocular pressure changes the experiment with adult male Chinchilla was used. In this lecture we present the design and synthesis of novel drug-like aromatic sulfonamides, namely (4-sulfamoyl-N-(3-morpholinopropyl) benzamide, N-(3-morpholinopropyl)benzene-1,4-disulfonamide, N-(4-diethylaminoethoxybenzyl)benzene-1,4-bis(sulfonamide) and their hydrochloride salts. They exhibited favorable biological, structural, physicochemical and some pharmacokinetic properties comparable to those obtained for therapeutically useful acetazolamide, dorzolamide and brinzolamide. The solid-state structure of novel aromatic sulfonamides has been examined by X-ray crystallography. Methods of theoretical medicinal chemistry were applied for structural characterization of these compounds in the gas phase and water solution. Of particular interest are the molecular geometries of neutral and anionic species, acidities, and lipophilicities.

Data obtained allows us to assume, that new aromatic sulfonamides may represent novel class of compounds for the discovery of new effective antiglaucoma drugs.