Design, Synthesis, In Vitro and In Vivo Evaluation of Novel Anti-Alzheimer's (1E,4E)-1,5-Bis[(het)aryl]penta-1,4-dien-3-one Derivatives
Abstract
Background/Objectives: Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative condition characterized by neurofibrillary tangles, neuronal loss, cognitive impairment, and accumulation of β-amyloid plaques. Considering the limitations of current treatments, which present adverse effects and only alleviate symptoms without modifying disease progression, there is an urgent need for new therapeutic approaches. This study aimed to investigate the neuroprotective potential of synthetic derivatives of (1E,4E)-1,5-bis[(het)aryl]penta-1,4-dien-3-ones, focusing on the inhibition of the cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets directly related to the cholinergic deficit observed in AD. Methods: The compounds were initially synthesized by aldol condensation reactions, with subsequent physicochemical characterization. They were then subjected to in silico assays that demonstrated high binding affinity to the active sites of AChE and BChE. The derivatives were evaluated in vitro for their inhibitory activity on these enzymes and in vivo in an experimental model of AD induced by streptozotocin in Wistar rats. Results: The synthesized derivatives showed favorable predicted interactions with the active sites of AChE and BChE, supporting their potential as cholinesterase inhibitors. In vitro assays demonstrated inhibitory activity against both enzymes, with selected derivatives showing improved activity compared with the…
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