Neuroprotective and Cholinergic Properties of Multifunctional Glutamic Acid Derivatives for the Treatment of Alzheimer's Disease

Novel multifunctional compounds have been designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease (AD). With an L-glutamic moiety as a suitable biocompatible linker, three pharmacophoric groups were joined: (I) an N-benzylpiperidine fragment selected to inhibit acetylcholinesterase by interacting with the catalytic active site (CAS), (2) an N-protecting group of the amino acid, capable of interacting with the acetylcholinesterase (AChE)-peripheral anionic site (PAS) and protecting neurons against oxidative stress, and (3) a lipophilic alkyl ester that would facilitate penetration into the central nervous system by crossing the blood-brain barrier. At submicromolar concentration, they inhibit ACNE and butyrylcholinesterase (BuChE) of human origin, displace the binding of propidium iodide from the PAS of ACNE, and could thus inhibit A beta aggregation promoted by ACNE. They also display neuroprotective properties against mitochondrial free radicals, show low toxicity, and could be able to penetrate into the CNS.