Multi-targeting aurones with monoamine oxidase and amyloid-beta inhibitory activities: Structure-activity relationship and translating multi-potency to neuroprotection - 06/01/19
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Graphical abstract |
Two multi-targeting aurones are identified: 2-2 with AChE and MAO-B inhibitory activities and 4-3 with AChE- and Aβ-inhibiting properties. The more drug-like 4-3 significantly protects against both Aβ- and oxydopamine-induced toxicity in Caenorhabditis elegans models of neurodegeneration.
Highlights |
• | Aurone 2-2 shows MAO-B inhibition while 4-3 inhibits Aβ aggregation. |
• | Pyrrolidine bearing 6-methoxyaurone is important for MAO-B inhibition. |
• | The B-ring 3,4,5-trimethoxyls of 4-3 are important for Aβ inhibition. |
• | 4-3 protects Caenorhabditis elegans against Aβ- and 6-OHDA-induced neurotoxicities dose-dependently. |
Abstract |
Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug-like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer’s disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Aβ) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Aβ aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Aβ inhibitor curcumin. Examination on the neuroprotective ability of the more drug-like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Aβ- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases.
Le texte complet de cet article est disponible en PDF.Keywords : Aurone, Multi-targeting, Monoamine oxidase, Amyloid-beta, Caenorhabditis elegans
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Vol 110
P. 118-128 - février 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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