Carbonic Anhydrase II as Target for Drug Design

Inhibition of CA II has pharmacological applications in the field of antiglaucoma and diuretic agents, for the treatment of altitude sickness, for some anticonvulsants, and probably against some cancer types. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of inhibitors targeting CA II. Recently the dithiocarbamates and xanthates, possessing a similar mechanism of action, were reported as a new class of inhibitors. The armamentarium of CA inhibitors (CAIs) targeting this isoform also includes phenols, polyamines, sulfocoumarins, and coumarins and their derivatives that act as prodrug inhibitors. Novel drug design strategies of all these types of derivatives have been reported based on the tail approach, for exploiting more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to compounds that discriminate between the different isoforms possessing active sites similar to CA II. Promising new compounds have been obtained by combining X-ray crystallography of enzyme-inhibitor adducts with novel synthetic approaches for generating chemical diversity. The sulfonamide-nitric oxide (NO)-donating hybrid drugs and the sulfonamides incorporating prostaglandin PGF2α analogs were reported as effective antiglaucoma investigational agents. Tolsultazolamide is a new agent for the prophylaxis and treatment of altitude sickness. No new diuretics or anticonvulsants were reported during the last decades, but such old-generation derivatives may be repositioned for alternative biomedical applications, such as benzothiazide, a clinically used diuretic with potent anticancer effects.