Potent inhibition of acetylcholinesterase by sargachromanol I from Sargassum siliquastrum and by selected natural compounds

Six hundred forty natural compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Of those, sargachromanol I (SCI) and G (SCG) isolated from the brown alga Sargassum siliquastrum, dihydroberberine (DB) isolated from Coptis chinensis, and macelignan (ML) isolated from Myristica fragrans, potently and effectively inhibited AChE with IC₅₀ values of 0.79, 1.81, 1.18, and 4.16 µM, respectively. SCI, DB, and ML reversibly inhibited AChE and showed mixed, competitive, and noncompetitive inhibition, respectively, with K_i values of 0.63, 0.77, and 4.46 µM, respectively. Broussonin A most potently inhibited BChE (IC₅₀ = 4.16 µM), followed by ML, SCG, and SCI (9.69, 10.79, and 13.69 µM, respectively). In dual-targeting experiments, ML effectively inhibited Monoamine Oxidase B with the greatest potency (IC₅₀ = 7.42 µM). Molecular docking simulation suggested the binding affinity of SCI (-8.6 kcal/mol) with AChE was greater than those of SCG (-7.9 kcal/mol) and DB (-8.2 kcal/mol). Docking simulation indicated SCI interacts with AChE at Trp81, and that SCG interacts at Ser119. No hydrogen bond was predicted for the interaction between AChE and DB. This study suggests SCI, SCG, DB, and ML be viewed as new reversible AChE inhibitors and useful lead compounds for the development for the treatment of Alzheimer's disease.

Acetylcholinesterase; Butyrylcholinesterase; Docking simulation; Monoamine oxidase; Sargachromanol I.