Site-Activated Chelators Targeting Acetylcholinesterase and Monoamine Oxidase for Alzheimer’s Therapy

Chelators have the potential to treat the underlying cause of Alzheimer’s disease (AD), but their therapeutic use is hampered by their poor targeting and poor permeability to the brain and/or toxic effects. Here, we report a new strategy for designing site-activated chelators targeting both acetylcholinesterase (AChE) and monoamine oxidase (MAO). We demonstrated that our lead <b>2</b> inhibited both AChE and MAO <i>in vitro</i>, but with little affinity for metal (Fe, Cu, and Zn) ions. Compound <b>2</b> can be activated by inhibition of AChE to release an active chelator <b>M30</b>. <b>M30</b> has been shown to be able to modulate amyloid precursor protein regulation and β-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compound <b>2</b> was less cytotoxic and more lipophilic than the brain-permeable chelator <b>M30</b>. Our new strategy is relatively simple and generally produces small and simple molecules with drug-like properties; it thus holds a potential use in designing site-activated multifunctional chelators with safer and more efficacious properties for treating other metal-related diseases such as Parkinson’s disease and cancer where specific elimination of metals in cancer cells is required.