Cassia obtusifolia Linn. have been used to improve vision, inflammatory diseases, and as hepatoprotective agents and to promote urination from ancient times. In the present study, we investigated the influence of glycosylation of components of C. obtusifolia and structure-activity relationships (SARs) with respect to the inhibition of
acetylcholinesterase (AChE),
butyrylcholinesterase (BChE), and β-site
amyloid precursor
protein (APP)-cleaving
enzyme 1 (BACE1), which are related to
Alzheimer's disease (AD). All six C. obtusifolia-derived compounds,
rubrofusarin (1),
rubrofusarin 6-O-β-d-glucopyranoside (2),
rubrofusarin 6-O-β-d-gentiobioside (3), nor-
rubrofusarin 6-O-β-d-glucoside (4), isorubrofusarin 10-O-β-d-gentiobioside (5), and
rubrofusarin 6-O-β-d-triglucoside (6) showed promising inhibitory activity against AChE/BACE1. Compounds 3 and 4 showed most significant inhibition against AChE and BACE1, respectively. The SARs results emphasized the importance of gentiobiosyl moiety in the
rubrofusarin for AChE inhibition, whereas the presence of
hydroxyl group at C-8 and the glucosyl moiety at the C-6 position in the nor-
rubrofusarin appeared to largely determine BACE1 inhibition. Kinetics and docking studies showed the lowest binding energy and highest affinity for mixed-type inhibitors, 3 and 4. Hydrophobic bonds interactions and the number of hydrogen bonds determined the strength of the
protein-inhibitor interaction. These results suggest that C. obtusifolia and its constituents have therapeutic potential, and that the SARs of its active components are further explored with a view towards developing a treatment for AD.