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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 . 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.
This article was published in the following journal.
Name: Bioorganic chemistry
The isolation of bioactive compounds from natural sources is a key step in drug discovery and development, however, this procedure is usually expensive and difficult due to the complexity and the limi...
The isoquinoline alkaloids isolated from the genus Corydalis possess potent and diverse biological activities. Herein, a concise, divergent, and enantioselective route to access these natural products...
Four previously undescribed erythrinan alkaloids, 8α-acetonylerythristemine, 8α-acetonylerysotrine, 10β-hydroxy-11β-methoxyerysotramidine and 3-epierysotrine, one undescribed pyrrolidine derivativ...
Ten new bisbenzylisoquinoline alkaloids (1-10) and eight known analogues (11-18) were obtained from the roots of Stephania tetrandra. The structures of these compounds were determined by spectroscopic...
Natural protoberberine alkaloids were first identified and characterized as potent, selective and cellular active lysine specific demethylase 1 (LSD1) inhibitors. Due to our study, isoquinoline-based ...
This is a randomized control trial evaluating the efficacy of zanthoxylum nitidum tincture on preventing progression of paronychia caused by afatinib from grade 1 to grade 2/3. Enrolled pa...
The purpose of this study is to evaluate the clinical efficacy and safety of 10-weeks oral consumption of Zanthoxylum schinifolium seed Oil (ZSO) in patients with mild dry eye disease.
Goldenseal is a botanical natural product commonly used to self-treat symptoms of the common cold and many digestive disorders. Goldenseal products typically contain the isoquinoline alkal...
In metastatic breast cancer (MBC) patients who have already received anthracyclines, taxanes, antimetabolites and vinca-alkaloids and have developed drug resistance to these drugs, therape...
An multi-site, randomized, prospective study to compare the efficacy and safety of multi-target therapy as continuous induction and maintenance treatment versus CTX- Aza therapy.
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.
Neurology - Central Nervous System (CNS)
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