Zinc(II) complexation behaviour of sulfonamide-based enzyme inhibitors

Sulfonamide derivatives containing extrafunctional groups, such as hydroxamic acids, hydroxypyrimidinones and carboxylic acids, have been recently identified as inhibitors towards several zinc-containing enzymes, such as the matrix metalloproteinases (MMPs) and/or carbonic anhydrases (CAs). Since these inhibitors are supposed to bind the zinc ion at the active site, it was decided to study the zinc(II) complexation with a set of representative compounds in order to identify the most probable coordination modes and to find eventual relationships with the inhibitory properties. These studies were performed in aqueous solution, by potentiome-try and H-1 NMR spectroscopy, and in the solid phase, by infrared spectroscopy. The solution equilibrium studies indicate that these compounds present similar affinity for zinc (pZn approximate to 6). Under stoichiometric conditions, the formation of 1:1 metal complex species involves a preferential (O,O) coordination via the hydroxamic or hydroxypyrimidinone moieties, while the coordination via the sulfonamide groups could mainly be achieved under zinc excess conditions.