Kinetics and Molecular Docking Studies of 6-Formyl Umbelliferone Isolated from Angelica decursiva as an Inhibitor of Cholinesterase and BACE1.

Md Ali,Sung Seo,Jae Choi,Hyun Jung,Machireddy Reddy,Su Seong

doi:10.3390/molecules22101604

Abstract

Coumarins, which have low toxicity, are present in some natural foods, and are used in various herbal remedies, have attracted interest in recent years because of their potential medicinal properties. In this study, we report the isolation of two natural coumarins, namely umbelliferone (1) and 6-formyl umbelliferone (2), from Angelica decursiva, and the synthesis of 8-formyl umbelliferone (3) from 1. We investigated the anti-Alzheimer disease (anti-AD) potential of these coumarins by assessing their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Among these coumarins, 2 exhibited poor inhibitory activity against AChE and BChE, and modest activity against BACE1. Structure–activity relationship analysis showed that 2 has an aldehyde group at the C-6 position, and exhibited strong anti-AD activity, whereas the presence or absence of an aldehyde group at the C-8 position reduced the anti-AD activity of 3 and 1, respectively. In addition, 2 exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. A kinetic study revealed that 2 and 3 non-competitively inhibited BACE1. To confirm enzyme inhibition, we predicted the 3D structures of AChE and BACE1, and used AutoDock 4.2 to simulate binding of coumarins to these enzymes. The blind docking studies demonstrated that these molecules could interact with both the catalytic active sites and peripheral anionic sites of AChE and BACE1. Together, our results indicate that 2 has an interesting inhibitory activity in vitro, and can be used in further studies to develop therapeutic modalities for the treatment of AD.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with characteristic features of memory impairment, cognitive dysfunction, behavior disturbances, and deficits in activity of daily living [1]
We previously reported that coumarins from A. decursiva have promising anti-Alzheimer disease (anti-AD), anti-diabetic, antioxidant, and anti-inflammatory activity [15,16,18,19,20,21]
We evaluated the anti-AD potential of coumarins by assessing their ability to inhibit AChE, BChE, by aspartic protease β-secretase 1 (BACE1), and ONOO− -mediated tyrosine nitration

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with characteristic features of memory impairment, cognitive dysfunction, behavior disturbances, and deficits in activity of daily living [1]. AD poses a huge economic burden worldwide, because there is no cure for this disease, which becomes progressively worse and eventually leads to death [3]. Molecules 2017, 22, 1604 pathogenesis: the cholinergic hypothesis and the amyloid cascade hypothesis [4]. These two major hypotheses cannot explain all pathological pathways of AD. AD has been reported to be highly associated with cellular oxidative stress, including augmentation of protein oxidation, protein nitration, and accumulation of amyloid-β peptide (Aβ) [6].

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Conclusion