1‐Aryl‐6,7‐Dimethoxy‐3,4‐Dihydroisoquinoline‐2(1 <i>H</i> )‐Sulfonamides as hCA XII Selective Inhibitors: Experimental and Theoretical Studies to Interrogate the Isoform Selectivity

Human carbonic anhydrase XII (hCA XII) represents an important pharmacological target for different types of cancer. hCA XII plays a crucial role in regulating both extracellular and intracellular pH, thereby influencing cancer cell proliferation, invasion, growth, and metastasis. Although the interaction features of hCA inhibitors (hCAIs) with the catalytic site of distinct hCA isoforms are generally well described, the lack of selectivity remains a major challenge. In a previous work, we have reported a series of 1‐aryl‐6,7‐dimethoxy‐3,4‐dihydroisoquinoline‐2(1 H )‐sulfonamides displaying weak activity against the ubiquitous hCA I and hCA II, thus emerging as hCAIs that may be free of unwanted side‐effects. Herein, further evaluation of their CA inhibitory effects allowed to disclose three potent hCA XII inhibitors at low nanomolar concentrations ( K i values ranging from 5.5 to 6.5 nM). Additionally, they showed remarkable isoform selectivity compared with the well‐known inhibitor SLC‐0111, currently in clinical trials as an antitumor agent. Crystallography analyses and computational studies clarified the molecular basis of this behavior and provided valuable insights for the rational design of selective inhibitors targeting hCA XII.