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

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.

Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer’s Disease

“…Therefore, it is not surprising the good activity of compounds 2 – 5 , which show an IC 50 in the low micromolar range (6.86 to 11.4 µM) without a significant difference between each other. These data are comparable with those recently reported by Ali et al about the activities of umbelliferone (AChEi as means ± SEMs of triplicate experiments =105.48 ± 0.57 µM), 6-formyl-umbelliferone (16.70 ± 1.62 µM), and 8-formyl-umbelliferon (19.13 ± 0.57 µM) isolated from Artemisia decursiva [ 40 ].…”

“…Considering that, when exploring multi-target ligands, the activities are not expected to be very high on each target, at least in the preliminary stage of research, the potency of our selected and tested compounds (in particular 1 and 3 ) in the low-medium micromolar range can be considered as a good result. Among the already mentioned works, Ali et al tested their compounds on BChE and BACE1 with a good inhibitory effect in particular for 6-formyl-umbelliferone [ 40 ]. For both research groups, these results will be the starting point for exploring the possibility to increase the activities and obtain new and more efficient chemical entities, through studies of Structure-Activity Relationships (SARs).…”

Crystal structure of 2-((tert-butyldimethylsilyl)oxy)-5-methylisophthalaldehyde, C15H22O3Si

“…Compounds with formyl group have a wide range of applications in the synthesis of functional organic molecules such as fluorescent dyes [5][6][7][8], bioactive molecules [9][10][11] and photoelectric materials [12]. Formyl groups can be oxidized to carboxyl groups and reduced to alcohol for further reaction.…”

“…-O(3), Si(1)-C(10), Si(1)-C(11), Si(1)-C(12), and O(3)-C(2) bond lengths are found to be 1.6802(13) Å, 1.858(2) Å, 1.858(2) Å, 1.8740(19) Å, and 1.369(2) Å, respectively, which are within the range expected for similar single bonds. The bond lengths of O(1)-C(7) and O(2)-C(8) are found to be 1.202(3) and 1.201(2) Å, respectively, in accordance with a typical carbonyl double bond.…”

Chemical Diversity of β-Secretase Inhibitors From Natural Resources

“…Ali et al isolated umbelliferones from Angelica decursiva and evaluated their inhibitory activities against β-secretase as an indicator of anti-AD activity. 20 Among the compounds tested, 6-formyl umbelliferone showed the most potent inhibitory activity against β-secretase with an IC 50 value of 1. gallotannins contained in fruits of Cornus officinalis. 22 Among them, 1,2,3,6-tetra-Ogalloyl-βd-glucose showed a potent inhibitory effect on β-secretase with an IC 50 value of 20.2 µM in a noncompetitive manner ( Figure 21).…”