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

New arylbenzofuran derivatives were designed, synthesized, and evaluated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Five hybrid compounds (<b>31</b>-<b>35</b>) feature a 2-phenylbenzofuran core linked via a heptyloxy spacer to an <i>N</i>-methylbenzylamine moiety, to enhance interactions within the active site of BChE. Biological evaluation revealed that brominated derivatives <b>34</b> and <b>35</b> showed the highest cholinesterases (ChE) inhibition compared to their chlorinated analogs, with compound <b>34</b> 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.