Umbelliferone derivatives exert neuroprotective effects by inhibiting monoamine oxidase A, self-amyloidß aggregation, and lipid peroxidation.

Umbelliferone has been demonstrated to have a wide range of biological activities. However, the effect of incorporating a formyl moiety in the umbelliferone scaffold has not been investigated. In this paper, we investigated the inhibitory activity of six coumarins, namely umbelliferone (1), 6-formyl umbelliferone (2), 8-formyl umbelliferone (3), umbelliferone-6-carboxylic acid (4), esculetin (5), and scopoletin (6) against human monoamine oxidases (hMAOs), self-amyloid ß (Aß) aggregation, and lipid peroxidation. We found that all compounds had high selectivity for hMAO-A in comparison with hMAO-B. Among the compounds, 2 exhibited the highest hMAO inhibitory activity with an IC50 value of 3.23 µM for hMAO-A and 15.31 µM for hMAO-B. Enzyme kinetic analysis showed that 2 and 3 were competitive hMAO inhibitors. In silico hydrated molecular docking simulations revealed that the coumarins interacted with substrate-binding site residues of the enzymes and the isoalloxazine ring of FAD. In addition, formyl coumarins 2 and 3 significantly inhibited lipid peroxidation in rat brain homogenates and self-Aß25-35 aggregation compared to other derivatives. These represent the first experimental and modelling data for hMAO-A/B inhibition by umbelliferone derivatives. Together, the data suggest that introduction of a formyl moiety in the 7-hydroxycoumarin scaffold, especially at the 6 position, plays an important role in the inhibition of hMAOs, Aß self-aggregation, and lipid peroxidation. Umbelliferone derivative 2 is a promising therapeutic lead scaffold for developing anti-neuropsychiatric disorder drugs that function via selective hMAO-A inhibition.

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

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 ß-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.