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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.

In recent years, Cassia seed extract has been reported as a neuroprotective agent in various models of neurodegeneration, mainly via an antioxidant mechanism. However, no one has previously reported the effects of Cassia seed extract and its phytochemicals on human monoamine oxidase (hMAO) enzyme activity. The seed methanol extract, the solvent-soluble fractions, and almost all isolated compounds displayed selective inhibition of hMAO-A isozyme activity. Interestingly, compounds obtusin (3), alaternin (8), aloe-emodin (9), questin (12), rubrofusarin (13), cassiaside (15), toralactone 9-O-β-gentiobioside (26), and (3S)-9,10-dihydroxy-7-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-benzo[g]isochromene-3-carboxylic acid 9-O-β-d-glucopyranoside (38) showed the most promising inhibition of the hMAO-A isozyme with IC50 values of 0.17–11 μM. The kinetic study characterized their mode of inhibition and molecular docking simulation predicted interactions with Ile-335 and Tyr-326 in support of the substrate/inhibitor selectivity in respective isozymes. These results demonstrate that Cassia seed extract and its constituents inhibit hMAO-A enzyme activity with high selectivity and suggest that they could play a preventive role in neurodegenerative diseases, especially anxiety and depression.

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