Exploring heterocyclic scaffolds in carbonic anhydrase inhibition: a decade of structural and therapeutic insights

Heterocyclic compounds represent a prominent class of molecules with diverse pharmacological activities. Among their therapeutic applications, they have gained significant attention as carbonic anhydrase (CA) inhibitors, owing to their potential in the treatment of various diseases such as epilepsy, cancer and glaucoma. CA is a widely distributed zinc metalloenzyme that facilitates the reversible interconversion of carbon dioxide and bicarbonate. This reaction is essential for numerous physiological and pathological processes. In humans, CA exists in sixteen different isoforms, labeled hCA-I to hCA-XV, each distributed across various tissues and organs and involved in crucial physiological functions. Clinically utilized CA inhibitors, such as brinzolamide, dorzolamide and acetazolamide, exhibit poor selectivity, leading to undesirable side effects. A significant challenge in designing effective CA inhibitors is achieving balanced isoform selectivity, prompting the exploration of new chemotypes. This review compiles recent strategies employed by various researchers in developing CAIs across different structural classes, including pyrazoline, quinoline, imidazole, oxadiazole, pyrimidine, coumarin, chalcone, rhodanine, phthalazine, triazole, isatin, and indole. Additionally, the review summarizes structure-activity relationship (SAR) analyses, isoform selectivity evaluations, along with mechanistic and in silico investigations. Insights derived from SAR studies provide crucial directions for the rational design of next-generation heterocyclic CA inhibitors, with improved therapeutic efficacy and reduced side effects. To the best of our knowledge, for the first time, we have comprehensively summarized all known isoforms of CA in relation to various heterocyclic motifs. This review examines the use of different heterocycles as CA inhibitors, drawing on research published over the past 11 years. It offers a valuable resource for early-career researchers, encouraging further exploration of synthetic heterocycles in the development of CA inhibitors.