Tetrazole Is a Novel Zinc Binder Chemotype for Carbonic\nAnhydrase Inhibition

The\ntetrazole group is here proposed as a zinc-binding warhead\nfor the inhibition of the metalloenzyme carbonic anhydrases. A set\nof synthesized derivatives incorporating the tetrazole moiety were\nevaluated as inhibitors against a panel of human isoforms, exhibiting <i>K</i><sub>I</sub> values spanning between the submicromolar\nand low-to-medium micromolar ranges (0.62–19.6 μM). X-ray\ncrystallographic studies were conducted to gain insights into their\nmodes of binding to the target enzyme. These findings mark a significant\nadvancement in the search for inhibitory chemotypes other than classical\nsulfonamides.