Phosphorus versus Sulfur: Discovery of Benzenephosphonamidates as Versatile Sulfonamide‐Mimic Chemotypes Acting as Carbonic Anhydrase Inhibitors

The first zinc-binding group (ZBG) to have been identified as inhibitor of the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1) was the sulfonamide. From then on several classes of zinc-binders have been described. This work reports the benzenephosponamidates as a new chiral aromatic sulfonamide-mimic ZBG able to meet the requirements for effectively binding the enzyme active site. Several low micromolar CA I, II, VII, IX inhibitors were thus detected. Kinetic studies, QM-polarized ligand docking, and MM-GBSA in silico methods were used to characterize this newly identified CA inhibitor chemotype.