Drug Design of Carbonic Anhydrase Inhibitors

Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and play essential roles in numerous physiological and pathological processes. Over the past decades, carbonic anhydrase inhibitors (CAIs) have emerged as valuable therapeutic agents for the treatment of a variety of human disorders, including glaucoma, epilepsy, altitude sickness, and, more recently, cancer and infectious diseases. This chapter provides a comprehensive overview of the principles and strategies underlying the rational design and synthesis of CA inhibitors. The two fundamental medicinal chemistry approaches for CAI development, the "ring approach" and the "tail approach," are discussed in detail, emphasizing the versatility and effectiveness of these strategies in optimizing binding affinity and enhancing isoform selectivity. Both classical zinc-binding inhibitors, such as sulfonamides and related chemotypes, and nonclassical inhibitors acting through alternative mechanisms are discussed. Among nonclassical inhibitors, particular attention is devoted to natural product-derived scaffolds, such as coumarins and polyamines, which have gained considerable interest due to their selective inhibition of the tumor-associated isoforms hCA IX/hCA XII, and hCA IV, respectively. The chapter also evaluates the increasing number of recently reported nonclassical chemotypes for which X-ray crystal structures in adduct with the enzymes are however not available. Finally, an overview of the main synthetic methodologies employed for the preparation of the different classes of CA inhibitors is presented, providing practical insights into the chemical strategies most commonly used in this field.