Coumarins as Carbonic Anhydrase Inhibitors

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes and relevant drug targets with many medicinal chemistry applications. Their classes of inhibitors are in clinical use as diuretics, or drugs for the management of glaucoma, epilepsy, obesity, tumors and infectious diseases. Among the inhibitors discovered so far, coumarins constitute an interesting class. They undergo CA-catalyzed hydrolysis and act as “prodrug inhibitors”, forming 2-hydroxy-cinnamic acids, which bind at the entrance of the enzyme active site, which has a relevant variability of amino acid residues among the different CA isoforms present in mammals, humans included. Coumarins act as isoform-selective CA inhibitors against pharmacologically relevant enzymes, such as the tumor-associated CA IX and XII. Coumarins present as metabolites in many species of bacteria, fungi, plants and ascidians showed relevant CA inhibitory properties and were used as leads for obtaining synthetic derivatives with enhanced enzyme inhibitory action belonging to a variety of classes, such as polysubstituted coumarins on both rings, thiocoumarins, thioxocoumarins, sulfocoumarins, etc.

Keywords: Carbonic Anhydrase, Coumarin, Prodrug Inhibitor, Sulfocoumarins, Thioxocoumarins, Tumors.