The CA inhibitory properties of numerous metal sulfonamide complexes mentioned here have been investigated in detail, mostly against the red cell isozymes hCA I and hCA II, but in some cases also against the membrane-bound isozyme bCA IV (h = human, b = bovine isozyme; reviewed in Alzuet et al. 1994c and Supuran 1994). Such studies surprisingly indicated that the metal complexes are 10 to 100 times more potent inhibitors of these isozymes as compared to the corresponding parent sulfonamides, making them among the most potent CAIs ever reported, with inhibition constants in the low nanomolar-picomolar range (Alzuet et al. 1994c; Supuran 1994). It is believed that this powerful inhibition is due to a dual mechanism of action of the complexes, through sulfonamide anions and metal ions obtained in dilute solution by dissociation of the coordination compounds (Luca et al. 1991). Sulfonamidate anions formed this way then bind to the Zn(II) ion within the enzyme active site, whereas the metal ions block the proton shuttle residues of CA, for instance His 64 for hCA II (Alzuet et al. 1994c; Supuran 1994; Supuran et al. 2003).
As a consequence of these very powerful enzyme inhibitory properties, several interesting applications have been reported for some metal complexes of heterocyclic sulfonamides possessing strong CA inhibitory properties. Thus, some Zn(II) and Cu(II) complexes of heterocyclic sulfonamides of type 6.20 to 6.25 and 6.28, 6.29 were very efficient intraocular pressure (IOP) lowering agents when administered topically in normotensive or glaucomatous rabbits, although most of the parent sulfonamides from which they were obtained do not show topical antiglaucoma activity (Supuran et al. 1998a, 1999; Briganti et al. 2000; Scozzafava et al. 2001, 2002). The observed topical activity has been explained by a modulation by the metal ion on the physicochemical properties of the complex, which in some cases becomes more polar and thus penetrates better though the cornea to inhibit ciliary processes CAs, thereby reducing elevated IOP in animal models of glaucoma (Supuran et al. 1998a, 1999; Briganti et al. 2000; Scozzafava et al. 2001, 2002).
Some Al(III) complexes, such as the benzolamide complex, act as efficient antisecretory agents in dogs. It has been proposed that the Zn(II), Mg(II) and Al(III) sulfonamide complexes might constitute a new class of antiulcer agents (Scozzafava et al. 2000).
It has been reported that copper(II) complexes of acetazolamide and methazola-mide are potent anticonvulsant agents. Their activity is higher than that shown by the parent sulfonamides (Alzuet et al. 1994b).
Mastrolorenzo et al. (2000a, 2000b) reported that some silver(I) complexes of sulfonamide CAIs, structurally related to acetazolamide and benzolamide (possessing potent CA inhibitory properties), also show very strong antifungal properties, explaining the use of such pharmacological agents for the treatment of burns.
All these data show that the metal complexes of sulfonamide CAIs have a largely unexplored potential for the design of pharmacological agents with a host of biological activities. By choosing different metal ions and diverse sulfonamides, it is possible to fine tune the biological activity in a manner rarely attainable by other classical techniques of drug design.
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