# 2-Arylbenzofurans as Selective Cholinesterase Inhibitors: Design, Synthesis, and Evaluation as Alzheimer’s Disease Agents

## TL;DR

Scientists designed new compounds that inhibit enzymes linked to Alzheimer's disease and found some are effective and non-toxic.

## Contribution

The study introduces new 2-arylbenzofuran compounds with dual cholinesterase inhibition and antioxidant properties for Alzheimer’s treatment.

## Key findings

- Brominated derivatives 34 and 35 showed highest inhibition of AChE and BChE with IC50 values of 27.7 μM and 0.7 μM respectively.
- Compound 34 demonstrated significant antioxidant activity in SH-SY5Y cells exposed to hydrogen peroxide.
- ADMET predictions suggest favorable pharmacokinetic properties including drug-likeness and oral bioavailability.

## Abstract

New arylbenzofuran derivatives were designed, synthesized, and evaluated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Five hybrid compounds (31–35) feature a 2-phenylbenzofuran core linked via a heptyloxy spacer to an N-methylbenzylamine moiety, to enhance interactions within the active site of BChE. Biological evaluation revealed that brominated derivatives 34 and 35 showed the highest cholinesterases (ChE) inhibition compared to their chlorinated analogs, with compound 34 showing the highest activity for both AChE (IC50 = 27.7 μM) and BChE (IC50 = 0.7 μM). These compounds proved to be non-cytotoxic and demonstrated significant antioxidant activity in SH-SY5Y cells exposed to hydrogen peroxide (H2O2), highlighting their potential to mitigate oxidative stress: a key pathological factor in Alzheimer’s disease. Structural activity analysis suggests that bromine substitution at position 7 and the presence of a seven-carbon linker are critical for dual ChE inhibition and selectivity towards BChE. ADMET prediction indicates favorable pharmacokinetic properties, including drug-likeness and oral bioavailability. Overall, these findings highlight the potential of the 2-arylbenzofuran as a promising scaffold for multitarget-directed ligands in Alzheimer’s disease therapy.