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Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) that affects mainly aged population. AD is characterized by a pronounced alteration of the cholinergic system and deficit of cholinergic function in the brain. Most currently prescribed AD drugs aim to increase the level of acetylcholine (ACh) in the brain by inhibiting acetylcholinesterase (AChE). Design of novel pyrrolizine derivatives, having the same pharmacophoric features as donepezil was performed. Molecular modeling techniques were used to support the design of these compounds as potential acetylcholinesterase inhibitors. The newly designed compounds were in vitro evaluated for their AChE and BuChE inhibitory activities and the mechanism of enzyme inhibition was explored by kinetic study. The ability of compounds to inhibit the self-induced AÝ aggregation compared with curcumin was done by ELISA. Neuroprotective effects in scopolamine-induced cognitive impairment model in mice were performed for the most active compounds after proving their safety against human neuroblastoma (SH-SY5Y) and normal human hepatic (THLE2) cell lines