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Alzheimer’s Disease (AD) is associated with low levels of acetylcholine in brain areas related to memory, learning and cognition. One current strategy for AD treatment, is based on the design of new cholinesterase inhibitors that directly modulate cholinergic transmission through the inhibition of the enzyme acetylcholinesterase (AChE). Our approach in this work was based on the synthesis and pharmacological evaluation of a new series of thalidomide-donepezil hybrids as new inhibitors of AChE, with potential neuroprotective and anti-inflammatory properties. The molecular design was based on the combination of a phthalimide fragment from thalidomide, known for its anti-inflammatory properties, with a functionalized N-benzylpiperazine subunit from donepezil. The preliminary in vitro results and molecular docking led to the identification of compound PQM-189 as the most potent AChE inhibitor (IC50= 5.78 μM). Further on going evaluation of its selectivity and neurotoxicity could lead to a novel promising prototype candidate for the treatment of AD.
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