## 2 Zinc Binding Groups in Chelation Therapy
### Treatment of Alzheimer's Disease
In particular, six analogs (Figure 2) with other halides (F, Cl, and Br) instead of the labile I in various positions were synthesized, with the aim of improving the stability of the molecules and modulate the acidity of phenolic OH: they have EC\({}_{50}\) values comparable with CQ (2.3-5.2 uM), besides compounds **2d-2f** show an improved Cu and Zn ionophore capacity. The introduction of radiolabeled \({}^{18}\)F makes them potential PET biomarkers [31]. The use of tetradentate ligands is another possible strategy to increase the protection against A\(\beta\) precipitation in AD. One such ligand, containing two 8-hydroxyquinoline (8-HQ) moieties covalently linked is shown in Figure 3. This molecule in particular can form coordinating complexes with Zn\({}^{2+}\) and Cu\({}^{2+}\), in which both quinolines chelate metal ions. The linker is a methylene at the C2 position of each quinoline, so this compound is symmetric and without chiral centers. Both the ligand and its Cu\({}^{2+}\) and Zn\({}^{2+}\) complexes are small, neutral at physiological pH, and hydrophobic: these characteristics facilitate the crossing of the BBB, an already mentioned essential requirement for the compound's action against A\(\beta\) aggregation in Alzheimer's disease. Consequently, it can be considered a good starting point for the development of tetradentate ligands as therapeutic agents. [32]. Moreover, a series of quinoline-indole derivatives, based on the combination of an indole moiety with a CQ-derived one, was recently developed. This series produced compound WI-1758 (shown in Figure 4), endowed with excellent antioxidant activity, BBB penetration, and inhibition of A\(\beta\) self-induced aggregation. WI-1758 is also able to chelate Cu\({}^{2+}\), Zn\({}^{2+}\), Fe\({}^{2+}\), and Fe\({}^{3+}\). WI-1758 hydrochloride has a good pharmacokinetic profile with an oral bioavailability of 14.1% and the ability to permeate BBB in vivo (LogBB value of \(-0.19\)), besides its chronic oral administration ameliorated deficits in APP/PS1 AD mice and reduced A\(\beta\) deposits [33]. Figure 3: Tetradentate ligand designed by [PERSON] et al. [32]. Figure 2: Analogs of clioquinol (CQ). X=Cl, Br, I [31]. Another recent approach aimed to combine the antioxidant and neuroprotective properties of (R)-alpha-lipoic acid (LA) and the chelating capacity of 8-HQ, resulting in a novel multitarget ligand (**5a**, in Figure 5), with antioxidant, chelating and neuroprotective properties for the treatment of neurodegenerative disorders, such as AD and PD [34]. The 8-HQ derivative 5-hydroxymethyl-8-hydroxyquinoline is linked to two molecules of LA via two ester bonds increasing its lipophilicity and it can cross plasma membranes, releasing HQ and two molecules of LA. This compound seems to be better than the single LA and HQ for neuroprotective and antioxidant activities [34]. Another 8-HQ analog, with the hydroxymethyl moiety linked to the sulfhydryl group of a glutathione tripeptide (GSH), was recently developed and displayed antioxidant activity (**5b**, Figure 5). The increased lipophilicity of the molecule is caused by the conjugation of the GSH's free cysteine to the HQ group. In addition to the antioxidant activity, the coordination properties of this GS(HQ)H toward Zn\({}^{2+}\), and Cu\({}^{2+}\) were also studied. The K\({}_{\rm D}\) values calculated for the Cu\({}^{2+}\) and Zn\({}^{2+}\) ligand investigated systems were 280 pm and 0.57 mm, respectively. These values suggest that GS(HQ)H is only partially able to remove copper from the A\(\beta\) once formed [35]. In order to tackle the multifactorial etiopathogenesis of AD, several efforts have been made in recent years to find multitarget anti-AD drugs. One notable approach consisted in combining Acetylcholinesteraseerase (AChE) inhibition with other neuroprotective functions such as metal chelation. This was achieved via the development of hybrid molecules, combining a tacrine (TAC) unit or a moiety mimicking of donepezil (DPZ) benzylpiperidine with Zn\({}^{2+}\) and Cu\({}^{2+}\) chelating moieties.