Carbonic anhydrase inhibition with natural products: novel chemotypes and inhibition mechanisms

Five genetically distinct classes of carbonic anhydrases (CAs, EC 4.2.1.1) are present in organisms all over the phylogenetic tree (alpha-, beta-, gamma-, delta-, and zeta-families). These metalloenzymes catalyze CO(2) hydration to bicarbonate and protons. Inhibition of alpha-CAs from vertebrates, including humans, with sulfonamides was exploited clinically for decades for various classes of diuretics and systemically acting antiglaucoma agents, whereas newer inhibitors are used as topically acting antiglaucoma drugs, anticonvulsants, antiobesity, antipain and antitumor agents/diagnostic tools. Recently, novel interesting chemotypes, in addition to the sulfonamide and sulfamate were discovered, many of which are based on natural products, such as phenols/polyphenols, phenolic acids, and coumarins. Their detailed mechanism of inhibition has been explained by means of kinetic and X-ray crystallographic studies, and can be used for the rational drug design of other agents. Possible applications for these new chemotypes in drug design of CA inhibitors are envisaged and discussed in detail in this review.