Carbonic anhydrase inhibitors. Metal complexes of 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide with topical intraocular pressure lowering properties: The influence of metal ions upon the pharmacological activity

Metal complexes of a sulfonamide possessing strong carbonic anhydrase (CA) inhibitory properties, 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide ( chlorazolamide) have been obtained from the sodium salt of the sulfonamide and the following metal ions: Mg(II), Zn(II), Mn(II), Cu(II), Co(II), Ni(II ), Be(II), Cd(II), Pb(II), Al(III), Fe(III) and La(III). The original sulfo namide and its complexes were assayed for the in vitro inhibition of three CA isozymes, CA I, II, and IV, some of which play a critical role in ocular fluid secretion. All these compounds (the sulfonamide and its metal comple xes) behaved as powerful inhibitors against the three investigated isozymes . The parent sulfonamide possessed an extremely weak topical pressure lower ing effect when administered as a 1-2% suspension into the rabbit eye, but some of its metal complexes, such as the Mg(II), Zn(II), Mn(II) and Cu(II) derivatives, lower intraocular pressure (IOP) in experimental animals very well. Ex vivo data showed a 99.5-99.9% CA II inhibition in ocular fluids an d tissues of rabbits treated with these agents, proving that the observed I OP lowering is due to CA inhibition. The influence of the different metal i ons upon the efficiency of the obtained complexes as pressure lowering drug s are discussed, leading to the possibility of designing more selective/pot ent pharmacological agents from this class.