A stilbenoid, rhapontigenin, isolated from the root of Rheum palmatum L. acts as a potent BACE1 inhibitor.

Seven compounds, comprising three anthraquinones and four stilbenoids, were isolated from the roots of Rheum palmatum L. These compounds include chrysophanol (1), aloe-emodin (2), aloe-emodin 8-O-β-D-glucopyranoside (3), desoxyrhapontigenin (4), rhapontigenin (5), desoxyrhaponticin (6), and piceatannol 3'-O-β-D-glucopyranoside (7). Among these, compound 5 showed potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activity with an IC value of 0.256 ± 0.008 μM, making it the most effective inhibitor obtained from herbal extracts to date, followed by compounds 3 (1.164 ± 0.108 μM), 6 (1.213 ± 0.193 μM), 7 (1.270 ± 0.130 μM), and 4 (2.028 ± 0.108 μM). Furthermore, kinetic analysis revealed that compound 5 acted as a mixed type-I inhibitor with an inhibition constant K value of 0.28 ± 0.07 μM. Notably, compound 2 exhibited potent Aβ aggregation inhibition with an IC value of 3.56 ± 0.19 μM, whereas compound 5 showed low Aβ aggregation inhibition with an IC value of >40 μM. The docking simulations revealed that compound 5 had a high binding affinity and interacted with TYR132, predicting it as a key residue for inhibition via hydrophobic interaction, and with THR133 via hydrogen bonding, in the flap region of BACE1. These results suggest that stilbenoids generally exhibit higher BACE1 inhibitory activity than that of anthraquinones, and that compound 5 (rhapontigenin) could be a promising candidate for the treatment of Alzheimer's disease as a potent BACE1 inhibitor.