Development of Potent
Carbonic Anhydrase Inhibitors Incorporating Both Sulfonamide and Sulfamide
Groups
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Abstract
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