Umbelliferone derivatives exert neuroprotective effects by inhibiting monoamine oxidase A, self-amyloidß aggregation, and lipid peroxidation.
Bioorg Chem
; 92: 103293, 2019 11.
Article
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| MEDLINE
| ID: mdl-31557622
ABSTRACT
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⯵M for hMAO-A and 15.31⯵M 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.
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Bases de datos:
MEDLINE
Asunto principal:
Umbeliferonas
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Peroxidación de Lípido
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Péptidos beta-Amiloides
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Fármacos Neuroprotectores
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Monoaminooxidasa
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Inhibidores de la Monoaminooxidasa
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2019
Tipo del documento:
Article