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The finding that acetylcholinesterase (AChE) colocalizes with β-amyloid (Aβ) and promotes and accelerates Aβ aggregation has renewed an intense interest in developing new multifunctional AChE inhibitors as potential disease-modifying drugs for Alzheimer's therapy. To this end, we have developed a new class of selective AChE inhibitors with site-activated chelating activity. The identified lead, HLA20A, exhibits little affinity for metal (Fe, Cu, and Zn) ions but can be activated following inhibition of AChE to liberate an active chelator, HLA20. HLA20 has been shown to possess neuroprotective and neurorescuing activities in vitro and in vivo with the ability to lower amyloid precursor holoprotein (APP) expression and Aβ generation and inhibit Aβ aggregation induced by metal (Fe, Cu, and Zn) ion. HLA20A inhibited AChE in a time and concentration dependent manner with an HLA20A-AChE complex constant (K(i)) of 9.66 × 10(-6) M, a carbamylation rate (k(+2)) of 0.14 min(-1), and a second-order rate (k(i)) of 1.45 × 10 (4) M(-1) min(-1), comparable to those of rivastigmine. HLA20A showed little iron-binding capacity and activity against iron-induced lipid peroxidation (LPO) at concentrations of 1-50 μM, while HLA20 exhibited high potency in iron-binding and in inhibiting iron-induced LPO. At a concentration of 10 μM, HLA20A showed some activity against monoamine oxidase (MAO)-A and -B when tested in rat brain homogenates. Defined restrictively by Lipinski's rules, both HLA20A and HLA20 satisfied drug-like criteria and possible oral and brain permeability, but HLA20A was more lipophilic and considerably less toxic in human SHSY5Y neuroblastoma cells at high concentrations (25 or 50 μM). Together our data suggest that HLA20A may represent a promising lead for further development for Alzheimer's disease therapy.

Selective Acetylcholinesterase Inhibitor Activated by Acetylcholinesterase Releases an Active Chelator with Neurorescuing and Anti-Amyloid Activities