A series of compounds incorporating both sulfonamide and sulfamide as zinc-binding groups (ZBGs) are reported as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Crystallographic studies on the complex of hCA II with the lead compound of this series, namely, 4-sulfamido-benzenesulfonamide, revealed the binding of two molecules in the enzyme active site cavity, the first one canonically coordinated to the zinc ion by means of the sulfonamide group and the second one located at the entrance of the cavity. This observation led to the design of elongated molecules incorporating these two ZBGs, separated by a linker of proper length, to allow the simultaneous binding to these different sites. The "long" inhibitors indeed showed around 10 times better enzyme inhibitory properties as compared to the shorter molecules against four physiologically relevant human (h) isoforms, hCA I, II, IX, and XII.