ABSTRACT
Unsubstituted aromatic sulfonamides have been known since the beginning of research in the field to inhibit carbonic anhydrases (CAs). From the 1950s, potent carbonic anhydrase inhibitors (CAIs) belonging to the heterocyclic sulfonamide class have been developed and led to the development of benzothiadiazine and high-ceiling diuretics as well as to the systemic antiglaucoma drugs acetazolamide, methazolamide,
heterocyclic, aromatic and bis-sulfonamide classes have been synthesized and investigated for their biological activity. In the late 1980s and early 1990s, the topically effective antiglaucoma CAIs were discovered, and two such drugs — dorzolamide and brinzolamide — are at present used clinically. Both have been designed by the ring approach, i.e., by investigating a very large number of ring systems incorporating sulfamoyl moieties. More recently, the tail approach has been reported for designing antiglaucoma CAIs with topical activity, but this approach can be extended for other applications of these pharmacological agents. It consists of attaching tails that induce the desired physicochemical properties to aromatic/heterocyclic sulfonamide scaffolds that possess derivatizableamino or hydroxy moieties. There has been progress in the discovery of inhibitors with higher affinity for a certain isozyme, although clear-cut isozyme-specific inhibitors are not available at present. Inhibitors selective for the membrane-associated (CAs IV, IX, XII and XIV) or the cytosolic isozymes are available, being either macromolecular compounds or the positively charged derivatives (of low molecular weight). CAIs possessing antitumor properties have also been discovered, with one such derivative — indisulam — in advanced clinical trials for treating solid tumors. CAIs with good anticonvulsant activity and several other biomedical applications have recently been reported. Some aliphatic sulfonamides show significant CA inhibitory properties, and compounds that possess zincbinding functions different from that of the classical one (of aromatic/heterocyclic sulfonamide type) have been reported, incorporating, among others, sulfamate, sulfamide and hydroxamate moieties. The field is in constant progress and can lead to the discovery of interesting pharmacological agents.
