Anti-Alzheimer’s Disease Activity of Bromophenols from a Red Alga, Symphyocladia latiuscula (Harvey) Yamada

[Image: see text] Symphyocladia latiuscula (Harvey) Yamada is a red alga with a myriad of bromophenols accompanied by a diverse array of biological activities. The main purpose of the present study was to characterize the anti-Alzheimer’s disease activity of bromophenols from S. latiuscula via inhibition of cholinesterases (AChE and BChE), β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and glycogen synthase kinase-3β (GSK-3β). The results of enzyme inhibition assays demonstrated 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) as potent inhibitors of aforementioned enzymes. Among the tested bromophenols, 3 showed multifold higher inhibition of all of the tested enzymes. Enzyme kinetics revealed different modes of inhibition, and in silico molecular docking simulation demonstrated the importance of the 7–OH group and bromine number for H-bond and halogen-bond interactions, respectively. Similarly, 1–3 at 20 μM concentration showed more than 50% inhibition of self-induced Aβ(25–35) aggregation. These results suggest that bromophenols from S. latiuscula, especially highly brominated (3), may represent a novel class of anti-Alzheimer’s disease drugs.