Structural Advances in Non‐Sulfonamide Carbonic Anhydrase Inhibitors: Insights Into Design, Bioactivity, and Binding Mechanism

ABSTRACT Carbonic anhydrases (CAs) belong to a set of metalloenzymes that facilitate the reversible catalytic hydration of CO 2 , playing crucial roles in pH regulation, respiration, and electrolyte secretion. Dysregulation of specific CA isoforms, particularly the human variants hCA I, II, IX, and XII, is implicated in multiple pathological conditions, including glaucoma, epilepsy, obesity, and various cancers. Traditionally, sulfonamide‐based inhibitors have dominated the therapeutic landscape; however, their limitations, such as off‐target side effects, poor selectivity for different isoforms, and allergic reactions, have galvanized interest in alternative scaffolds. This comprehensive review critically examines the burgeoning class of non‐sulfonamide inhibitors targeting hCA isoforms, focusing on the chemical diversity, binding mechanisms, and structure–activity relationships of recently developed phenols, carboxylic acids, coumarins, dithiocarbamates, and polyamines. Special attention is given to the advances in X‐ray crystallography and computational modeling that have illuminated binding modes distinct from classical sulfonamide interactions. By synthesizing the latest findings, this review aims to guide future efforts in the rational design of selective and efficacious non‐sulfonamide CA inhibitors for clinical application.