## 2 Zinc Binding Groups in Chelation Therapy
### Inhibition of Matrix Metalloproteinases
As an example, following this strategy, a novel class of compounds (Figure 10), consisting of pyrimidine compounds which possess a 1,2,4-triazoleol-3-yl group as a zinc binding group (ZBG) were recently developed and proved useful in the inhibition of MMP-13 up to the low nanomolar range, with high selectivity against MMP-2, -9 and -10. X-ray analysis of the complex shows that 1,2,4-triazoleol-yl moiety directly binds zinc, without chelation (with a ligand to metal molar ratio 4:1), differently from what can be supposed looking at the chemical structure [50]. On the other hand, [PERSON] and collaborators already identified in 2003 six new potential ZBGs (Figure 11) that will be useful for the subsequent development of MMP inhibitors able to bind Zn\({}^{2+}\) in MMPs pocket in a strong, bidentate way [51]. They found an alternative to hydroxamate through the study of the interaction of six different scaffolds with the tetrahedral zinc complex [(Tp\({}^{\text{Ph},\text{Me}}\))ZnOH], (Tp\({}^{\text{Ph},\text{Me}}\) = hydrotris(3,5-phenylmethyllypyrazol)]borate, Figure 10). Thanks to X-ray crystallography and IR and \({}^{1}\)H-NMR data, it was demonstrated that these ZBGs are able to interact with the metal through chelation [51]. Further development of this route led to a new class of compounds with a 1-hydroxypiperazine-2,6-dione (HPD) as the ZBG of choice for the inhibition of matrix metalloproteinases (Figure 12). HBD binds the catalytic Zn\({}^{2+}\) of MMPs in a bidentate way, such as the hydroxamic acids, but its  
Figure 11: Zinc binding groups (ZBGs) in [(Tp\({}^{\text{Ph},\text{Me}}\))Zn(ZBG)] complexes: 1-hydroxy-2(1H)-pyridinone (**11a**); 3-hydroxy-2(1H)-pyridinone (**11b**); 3-hydroxy-1-methyl-2(1H)-pyridinone (**11c**); 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone (**11d**); 1-hydroxy-2(1H)-pyridinethione (**11e**); 3-hydroxy- 2-methyl-4-pyrone (**11f**) [51]. Figure 10: General structure of pyrimidine-based compounds as MMP-13 inhibitors [50]. six-membered ring structure should give it greater stability and more resistance to hydrolysis, with, additionally, better pharmacokinetic properties [52]. The inhibition against a wide panel of MMPs was reported with IC\({}_{50}\) from the nanomolar to low micromolar range [52]. [PERSON] et al. synthesized instead the first series of 1-hydroxy-2-pyridinone-based sulfonamide inhibitors of both MMP-2 and MMP-9. These compounds show nanomolar potency in the enzyme assay. Moreover, one of the derivatives (Figure 13) demonstrates excellent pharmacokinetic properties in rats, with oral bioavailability and reduced brain edema caused by ischemia in mice [53]. Another example of an alternative to the hydroxamic acid as the ZBG, namely a hydroxypyrone moiety (with a supposed mechanism already reported in Figure 10), was developed by [PERSON] and collaborators [54]. In their series a terphenyl group interacts with the aminoacidic residues in the S\({}^{1}\) pocket of the MMP catalytic domain. In particular, the compound shown in Figure 14 exhibits an interesting potency and selectivity towards MMP-12 with an IC\({}_{50}\) in the nanomolar range (0.117 nM) with good-high selectivity against the other MMPs (it is more than 250 times more active then on MMP-1,-3,-7,-9,-10, and -13). Interestingly, it possesses also anti-inflammatory properties in vitro and in vivo [54]. Other innovative noncyclic but rigid scaffolds have been studied as inhibitors of MMP-2, MMP-3, and MMP-8: this particular moiety contains the CO-NH-OH groups necessary for zinc chelation. An Italian group [55], for example, demonstrated that the binding interactions of the hydroxamate (Figure 15, compound **15a**) can be maintained in a series of N-hydroxyurea derivatives (Figure 15, compound **15b-e**). In the first instance, the crystal structure of the complex with MMP-8 showed  
Figure 14: Best hydroxypyrone-based matrix metalloproteinases inhibitor (MMPI) developed by [PERSON] et al. [54]. Figure 12: 1-hydroxypiperazine-2,6-dione (HPD) derivatives [52]. Figure 13: Best inhibitor synthesized by [PERSON] et al.