Synthesis and biological activity of 2-phenylbenzofuran derivatives as butyrylcholinerase inhibitors

Alzheimer disease (AD) is an irreversible and progressive brain disorder characterized by progressive memory loss and a wide range of cognitive impairments. An accepted strategy towards its treatment is to restore the levels of acetylcholine by inhibiting cholinesterase enzymes, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). BChE activity progressively increases in patients with AD, while AChE activity remains unchanged or declines, with changes that become more and more pronounced during the disease course. Therefore, compounds that selectively interact with BChE might have a relevant role in treatment of patients with advanced AD.

Benzofuran scaffold has drawn considerable attention over the last few years due to its profound physiological and chemotherapeutic properties. In our recent study, a series of 2-phenylbezonfurans compounds were synthesized and their inhibition activity towards both the enzymes were investigated. These compounds showed no inhibition toward AChE while inhibited BChE with different efficiencies. In addition to biological assays, molecular dynamics simulations allowed highlighting the molecular basis of the selective BChE inhibition by the benzofuran scaffold.

Based on these previous results, in the current work we have designed new 2-benzofurans derivatives in order to increase the strength of enzyme inhibition. We have used the Wittig reaction as a key step of a good methodology for the efficient and general synthesis of a selected series of 2-phenylbenzofurans. For all the compounds of the series, the IC₅₀ values were determined.

In this scenario, our findings could be extended to design and develop new potentially therapeutic molecules, especially useful in neurodegenerative diseases.