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2-Arylbenzofuran-based molecules as multipotent Alzheimer's disease modifying agents
Stefano Rizzo1, Andrea Tarozzi, Manuela Bartolini
1Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
European Journal of Medicinal Chemistry
|November 21, 2012
Summary
New 2-arylbenzofuran compounds show promise for Alzheimer's disease (AD) treatment by inhibiting key targets like acetylcholinesterase and amyloid-beta aggregation. Some compounds also offer neuroprotection and interact with cannabinoid receptors.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- Alzheimer's disease (AD) pathogenesis is complex, necessitating multi-target therapeutic strategies.
- Previous research has explored various compounds for AD, but novel multi-functional agents are needed.
Purpose of the Study:
- To design, synthesize, and evaluate novel 2-arylbenzofuran derivatives as multi-target agents for Alzheimer's disease.
- To assess the inhibitory effects of these compounds on human acetylcholinesterase (AChE), human butyrylcholinesterase (BuChE), and amyloid-beta (Aβ) fibril formation.
- To investigate their neuroprotective potential against Aβ-induced toxicity, including neuronal viability, Aβ-cell binding, and reactive oxygen species (ROS) generation.
Main Methods:
- Synthesis of a focused library of 2-arylbenzofuran derivatives.
- In vitro evaluation of anticholinesterase activity against human AChE and BuChE.
- Assessment of Aβ fibril formation inhibition.
- Testing for neuroprotective effects against Aβ neurotoxicity and ROS production.
- Evaluation of cannabinoid receptor 1 (CB1) affinity and selectivity for selected compounds.
Main Results:
- Several synthesized 2-arylbenzofurans exhibited significant anticholinesterase activity, surpassing previous related compounds.
- Compounds demonstrated efficacy in inhibiting Aβ fibril formation and providing neuroprotection.
- Compounds 18 and 1 emerged as particularly promising multi-target agents.
- Compound 1 displayed notable selectivity and moderate affinity for the CB1 receptor.
Conclusions:
- The novel 2-arylbenzofurans represent a promising class of multi-target compounds for Alzheimer's disease therapy.
- Their ability to inhibit cholinesterases, prevent Aβ aggregation, and offer neuroprotection supports their therapeutic potential.
- The CB1 receptor interaction of compound 1 opens new avenues for neuroprotective strategies in AD research.
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