Carbonic anhydrase II (CAII) is a metalloenzyme responsible for the interconversion of carbon dioxide and bicarbonate, for which non-covalent inhibitors have been developed as treatments for glaucoma, oedema, and cancer. CAII inhibitors are typically based on aromatic sulfonamide pharmacophores, which interact with the Zn 2+ ion via the sulfonamide group. The HTC-D2B screen with CAII afforded four hits (2b-e) with modification yields of 66-75% (see Fig. ). Three of these hits contained an aromatic sulfonamide, consistent with known inhibitors, while one of the four (2c) was an aliphatic sulfonamide, of which there are few prior reports. These four compounds were the only primary sulfonamides in the library, and the remainder of the library gave an average modification yield of <1%, indicating negligible non-specific modification, and high specificity of the hit fragment interactions.