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Molecules 2017, 22(10), 1604; doi:10.3390/molecules22101604

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

Department of Food and Life Science, Pukyong National University, Busan 48513, Korea
Department of Chemistry, Pukyong National University, Busan 48513, Korea
Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 54896, Korea
These two authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 22 August 2017 / Revised: 21 September 2017 / Accepted: 21 September 2017 / Published: 24 September 2017
(This article belongs to the Special Issue Versatile Coumarins)
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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. View Full-Text
Keywords: Angelica decursiva; 6-formyl umbelliferone; coumarins; BACE1; cholinesterases; molecular docking Angelica decursiva; 6-formyl umbelliferone; coumarins; BACE1; cholinesterases; molecular docking

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MDPI and ACS Style

Ali, M.Y.; Seong, S.H.; Reddy, M.R.; Seo, S.Y.; Choi, J.S.; Jung, H.A. Kinetics and Molecular Docking Studies of 6-Formyl Umbelliferone Isolated from Angelica decursiva as an Inhibitor of Cholinesterase and BACE1. Molecules 2017, 22, 1604.

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