Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aβ aggregation.

07:00 EST 4th March 2020 | BioPortfolio

Summary of "Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aβ aggregation."

Multifactorial neurodegenerative disorders such as Alzheimer's disease (AD) are considered a growing public health problem due the rising incidence and low effectiveness of current treatments [6]. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new anti-AD drug candidates. Herein described natural isoquinoline alkaloids were investigated for multi-target activity on key mechanisms associated with the AD's pathogenesis, i.e. cholinergic depletion, beta amyloid (Aβ) aggregation and oxidative stress. Alkaloid isolation from root extract of Zanthoxylum rigidum was carried out using multi-step chromatography and TLC-bioautography against acetylcholinesterase (AChE) giving eight purified isoquinoline alkaloids. Isolated compounds were tested for inhibitory activity against cholinesterase (AChE and BChE), monoamine oxidase (MAO-A and B) and Aβ aggregation. Our study revealed two benzophenanthridine alkaloids, nitidine (5) and avicine (7), as the most potent multi-target candidates. Both showed dual cholinesterase inhibition, being more active against AChE over BChE, with IC values in sub-micromolar range in AChE. Kinetic analysis with cholinesterase showed, that both compounds are reversible-mixed inhibitors, where avicine (7) presented highest potency with K values of 0.063 µM (EeAChE), 0.511 µM (HrAChE) and 0.123 µM (EqBChE). In addition, these alkaloids presented moderate Aβ anti-aggregation activity and MAO-A inhibition with IC values between 0.5 and 2 µM. Our findings suggest that avicine (7) is a promising natural compound and multifunctional candidate representing a suitable starting point for the development of new therapeutic agents for Alzheimer's disease.


Journal Details

This article was published in the following journal.

Name: Bioorganic chemistry
ISSN: 1090-2120
Pages: 103722


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Medical and Biotech [MESH] Definitions

A plant genus of the family RUTACEAE. Most plants that are called Fagara are actually Zanthoxylum. Some members of Zanthoxylum are reclassified from ELEUTHEROCOCCUS, Melicope, and EVODIA. The twigs are used as dental brushing sticks (TOOTHBRUSHING).

A plant genus of the family PAPAVERACEAE that contains isoquinoline alkaloids.

A plant genus of the family FUMARIACEAE that contains fumariline and other isoquinoline alkaloids.

A plant genus of the family RANUNCULACEAE. Members contain isoquinoline alkaloids.

A plant genus of the family RANUNCULACEAE. Members contain BERBERINE and other isoquinoline ALKALOIDS.

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