Carbonic anhydrase inhibitors. Inhibition of the prokariotic beta and gamma-class enzymes from Archaea with sulfonamides

A detailed inhibition study of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the β- and γ-families from Archaea with sulfonamides has been performed. Compounds included in this study were the clinically used sulfonamide CA inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, valdecoxib, celecoxib, dorzolamide, sulfanilamide, dichlorophanamide, as well as sulfanilamide analogs, halogenated sulfanilamides, and some 1,3-benzenedisulfonamide derivatives. The two γ-CAs from Methanosarcina thermophila (Zn-Cam and Co-Cam) showed very different inhibitory properties with these compounds, as compared to the α-CA isozymes hCA I, II, and IX, and the β-CA from Methanobacterium thermoautotrophicum (Cab). The best Zn-Cam inhibitors were sulfamic acid and acetazolamide, with inhibition constants in the range of 63-96 nM, whereas other investigated aromatic/heterocylic sulfonamides showed a rather levelled behavior, with K _Is in the range of 0.12-1.70 μM. The best Co-Cam inhibitors were topiramate and p-aminoethyl-benzenesulfonamide, with K _Is in the range of 0.12-0.13 μM, whereas the worst one was homosulfanilamide (K _I of 8.50 μM). In the case of Cab, the inhibitory power of these compounds varied to a much larger extent, with sulfamic acid and sulfamide showing millimolar affinities (K _Is in the range of 44-103 mM), whereas the best inhibitor was ethoxzolamide, with a K _I of 5.35 μM. Most of these sulfonamides showed inhibition constants in the range of 12-100 μM against Cab. Thus, the three CA families investigated up to now possess a very diverse affinity for sulfonamides, the inhibitors with important medicinal, and environmental applications.