Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most predominant neurodegenerative disorder that is found in the elderly
We reported on the inhibitory activities of major chemical constituents that are isolated from C. obtusifolia against BACE1 and cholinesterase [18]
In order to evaluate the anti-AD potential of the isolated rubrofusarin and its five derivatives, we evaluated their abilities to inhibit AChE, BChE, and BACE1
Summary
Alzheimer’s disease (AD) is the most predominant neurodegenerative disorder that is found in the elderly. It has been reported that more than 46.8 million people suffer from AD, and that the associated annual medical costs exceed $818 billion. 131.5 million individuals would have AD in the year 2050 [1]. Life expectancy after clinical symptom onset is around 8.5 years [2]. Until now, there is no effective treatment that targets the underlying molecular causes of disease. The absolute pathophysiological mechanism of the disease is not clear, two hypotheses have been proposed, which are, the “cholinergic hypothesis” and the “amyloid hypothesis”. According to the cholinergic hypothesis, insufficiency of cholinergic functions in the brain results in the memory impairments. The use of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors (enzymes responsible for metabolic hydrolysis of acetylcholine), which increase
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