Site-activated multi target iron chelators with acetylcholinesterase (AChE) and monoamine oxidase (MAO) inhibitory activities for Alzheimer's disease therapy.

The first class of site-activated chelators with dual inhibition of acetyl-cholinesterase (AChE) and monoamine oxidase (MAO), rationally designed for simultaneously targeting the multiple pathogenic processes in Alzheimer's disease (AD) without significantly disrupting healthy metal metabolism in the body are discussed. It is demonstrated that the novel prochelator 2 was a selective and potent MAO-A inhibitor in vitro (IC50: 0.0077 ± 0.0007 μM) with moderate inhibition of MAO-B (IC50: 7.90 ± 1.34 μM). In vitro prochelator 2 also selectively inhibited AChE in a time-dependent manner and reach maximum inhibition of AChE after 2 h preincubation (IC50: 0.52 ± 0.07 μM for AChE, versus 44.90 ± 6.10 μM for BuChE). Prochelator 2 showed little affinity for metal (Fe, Cu, and Zn) ions until it bound to and was activated by AChE that is located predominately in the brain, releasing an active iron chelator M30. M30 is an efficient chelator for metal (Fe, Cu, and Zn) ions with the capabilities to suppress oxidative stress, to selectively inhibit MAO-A and B in the brain, and to regulate cerebral biometals dyshomeostasis in vivo; M30 is also a neuroprotective-neurorestorative chelator with a broad spectrum of activities against β-amyloid (Aβ) generation, amyloid plaques and neurofibrillary tangles (NFT) formation, and Aβ aggregation induced by metal (Cu and Zn) ions. Both M30 and prochelator 2 were not toxic to Human SH-SY5Y neuroblastoma cells at low concentrations, but prochelator 2 shows limited cytotoxicity, at high concentrations. Together, these data suggest that prochelator 2 is a promise lead for simultaneously modulating multiple targets in AD.