Chapter 10 - Mechanisms of action of carbonic anhydrase inhibitors: compounds that anchor to the zinc-bound nucleophile

Abstract

To date, there are several classes of compounds identified as carbonic anhydrase (CA) inhibitors. Their inhibition profile toward different isoforms is discussed here, considering the nature of the scaffold, occupancy, and physical properties (hydrophilicity or lipophilicity) of the substituents present on it. The selectivity issue between different isoforms is addressed, which has been the main challenge for designing effective CA inhibitors for decades. With the help of X-ray crystallography, the exploration of novel inhibition mechanisms of different chemotypes became a fascinating tool for the design of new inhibitors. Anchoring to the zinc-bound nucleophile species is one of the main mechanisms of CA inhibition, which led to interesting developments in the last years. We discuss here the nonclassic CA inhibitors possessing this inhibition mechanism, of the phenol, carboxylic acid, polyamine, sulfocoumarin, and the thioxocoumarin type.