Plants of the Amaryllidaceae family are promising therapeutic tools for human diseases and have been used as alternative medicines. The specific secondary metabolites of this plant family, called Amaryllidaceae alkaloids (AA), have attracted considerable attention due to their interesting pharmacological activities. One of them, galantamine, is already used in the therapy of Alzheimer's disease as a long acting, selective, reversible inhibitor of acetylcholinesterase. One group of AA is the montanine-type, such as montanine, pancracine and others, which share a 5,11-methanomorphanthridine core. So far, only 14 montanine-type alkaloids have been isolated. Compared with other structural-types of AA, montanine-type alkaloids are predominantly present in plants in low concentrations, but some of them display promising biological properties, especially in vitro cytotoxic activity against different cancerous cell lines. The present review aims to summarize comprehensively the research that has been published on the Amaryllidaceae alkaloids of montanine-type.

• Keywords
• Amaryllidaceae, alkaloids, biological activity, derivatives, montanine, montanine-type, pancracine,
• MeSH
• Amaryllidaceae Alkaloids chemistry   isolation & purification   pharmacology   MeSH
• Amaryllidaceae chemistry   metabolism   MeSH
• Antiprotozoal Agents chemistry   isolation & purification   pharmacology   MeSH
• Cholinesterase Inhibitors chemistry   isolation & purification   pharmacology   MeSH
• Phenanthridines chemistry   isolation & purification   pharmacology   MeSH
• Antineoplastic Agents, Phytogenic chemistry   isolation & purification   pharmacology   MeSH
• Galantamine chemistry   isolation & purification   pharmacology   MeSH
• Heterocyclic Compounds, 4 or More Rings chemistry   isolation & purification   pharmacology   MeSH
• Inhibitory Concentration 50 MeSH
• Isoquinolines chemistry   isolation & purification   pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Nootropic Agents chemistry   isolation & purification   pharmacology   MeSH
• Plant Extracts chemistry   MeSH
• Secondary Metabolism MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Antiprotozoal Agents MeSH
• Cholinesterase Inhibitors MeSH
• Phenanthridines MeSH
• Antineoplastic Agents, Phytogenic MeSH
• Galantamine MeSH
• hemanthamine MeSH Browser
• Heterocyclic Compounds, 4 or More Rings MeSH
• Isoquinolines MeSH
• montanine MeSH Browser
• Nootropic Agents MeSH
• pancracine MeSH Browser
• Plant Extracts MeSH

Nerine Herbert, family Amaryllidaceae, is a genus of about 30 species that are native to South Africa, Botswana, Lesotho, Namibia, and Swatini (formerly known as Swaziland). Species of Nerine are autumn-flowering, perennial, bulbous plants, which inhabit areas with summer rainfall and cool, dry winters. Most Nerine species have been cultivated for their elegant flowers, presenting a source of innumerable horticultural hybrids. For many years, species of Nerine have been subjected to extensive phytochemical and pharmacological investigations, which resulted in either the isolation or identification of more than fifty Amaryllidaceae alkaloids belonging to different structural types. Amaryllidaceae alkaloids are frequently studied for their interesting biological properties, including antiviral, antibacterial, antitumor, antifungal, antimalarial, analgesic, cytotoxic, and cholinesterase inhibition activities. The present review aims to summarize comprehensively the research that has been reported on the phytochemistry and pharmacology of the genus Nerine.

• Keywords
• Alzheimer’s disease, Amaryllidaceae, Nerine, Nerine bowdenii, antitumor activity, folk medicine,
• MeSH
• Amaryllidaceae Alkaloids pharmacology   MeSH
• Amaryllidaceae chemistry   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Ethnobotany * MeSH
• Humans MeSH
• Plant Extracts pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Cholinesterase Inhibitors MeSH
• Plant Extracts MeSH

In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman's spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood⁻brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer's disease.

• Keywords
• (+)-canadine, (+)-thalictricavine, blood–brain barrier permeability, cholinesterases, kinetic study, molecular docking,
• MeSH
• Acetylcholinesterase chemistry   drug effects   MeSH
• Alkaloids chemistry   pharmacology   MeSH
• Alzheimer Disease drug therapy   enzymology   MeSH
• Berberine analogs & derivatives   chemistry   pharmacology   MeSH
• Biological Transport drug effects   MeSH
• Butyrylcholinesterase chemistry   drug effects   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Corydalis chemistry   MeSH
• Disaccharides chemistry   pharmacology   MeSH
• Nitro Compounds chemistry   pharmacology   MeSH
• Blood-Brain Barrier drug effects   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Computer Simulation MeSH
• Protein Binding drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Alkaloids MeSH
• Berberine MeSH
• Butyrylcholinesterase MeSH
• canadine MeSH Browser
• Cholinesterase Inhibitors MeSH
• Disaccharides MeSH
• Nitro Compounds MeSH
• thalictricoside MeSH Browser

Twelve derivatives 1a-1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.

• Keywords
• Alzheimer’s disease, Amaryllidaceae, acetylcholinesterase, butyrylcholinesterase, docking studies, glycogen synthase kinase-3β inhibition, haemanthamine,
• MeSH
• Amaryllidaceae Alkaloids chemistry   metabolism   MeSH
• Alzheimer Disease metabolism   MeSH
• Amaryllidaceae chemistry   metabolism   MeSH
• Phenanthridines chemistry   metabolism   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Glycogen Synthase Kinase 3 beta metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Permeability MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Phenanthridines MeSH
• hemanthamine MeSH Browser
• Glycogen Synthase Kinase 3 beta MeSH
• Ligands MeSH

Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating a wide variety of well-known substances like glycogen synthase, tau-protein, and β-catenin. Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes. GSK-3β is one of the most attractive targets for medicinal chemists in the discovery, design, and synthesis of new selective potent inhibitors. In the current study, twenty-eight Amaryllidaceae alkaloids of various structural types were studied for their potency to inhibit GSK-3β. Promising results have been demonstrated by alkaloids of the homolycorine-{9-O-demethylhomolycorine (IC50 = 30.00 ± 0.71 µM), masonine (IC50 = 27.81 ± 0.01 μM)}, and lycorine-types {caranine (IC50 = 30.75 ± 0.04 μM)}.

• Keywords
• 9-O-demethylhomolycorine, Alzheimer’s disease, Amaryllidaceae alkaloids, caranine, glycogen synthase kinase-3β, masonine,
• MeSH
• Amaryllidaceae Alkaloids chemistry   pharmacology   MeSH
• Inhibitory Concentration 50 MeSH
• Protein Kinase Inhibitors chemistry   pharmacology   MeSH
• Glycogen Synthase Kinase 3 beta antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Drug Evaluation, Preclinical MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Protein Kinase Inhibitors MeSH
• Glycogen Synthase Kinase 3 beta MeSH