Benzofuran-Based Hybrid Compounds for the Inhibition of Cholinesterase Activity, β Amyloid Aggregation, and Aβ Neurotoxicity

Abstract

The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multitarget strategies to combat causes and symptoms. We therefore designed, synthesized, and tested new hybrid molecules linking a benzofuran ring to a N-methyl- N-benzylamine through a heptyloxy chain, affording a series of potential multifunctional drugs for AD. The cholinesterase inhibitory activity was extended to the inhibition of Abeta fibril formation for 1, 3, and 5. Compound 3 showed an additional neuroprotective effect.

Multifunctional Receptor-Directed Drugs for Disorders of the Central Nervous System

“…Another recent example of this concept is the development of benzofuran-based compounds that simultaneously inhibit acetylcholinesterase and prevent amyloid A␤ peptide aggregation. 16 This latter property is expected to prevent the formation of the most neurotoxic species of amyloid, while the inhibition of acetylcholinesterase would be expected to improve cognition. In the next section, examples will be provided of the various approaches we have used both to support the proof of concept of side-effect suppression with the use of promiscuous drugs, and the relevance of single molecules that have multiple drug targets.…”

Design, Synthesis and Evaluation of Genistein-polyamine Conjugates as Multi-functional Anti-Alzheimer Agents

“…Many factors have been found to be implicated in AD, such as low levels of acetylcholine, β-amyloid deposits, oxidative damage and metal ions, which seem to play significant roles in the disease 2 . Current treatment of AD focuses on increasing cholinergic neurotransmission in the brain by inhibiting cholinesterases (ChEs) with medicines including tacrine, donepezil, rivastigmine and galantamine 3 . Unfortunately, the potential effectiveness offered by the above inhibitors is often limited by their side effects.…”

Acetylcholinesterase Inhibitory Effect of 3-(1h-Indol-3-Yl)-1, 3-Diphenylpropan-1-One Derivatives

“…Four AChEI are approved by food and drug administration, they are tacrine, donepezil, rivastigmine, and gallantamine [9,10]. Unfortunately, the potential effectiveness is often limited by the side effects [11].…”