Alzheimer's disease (AD) is the most common cause of dementia in elderly people; currently, there is no efficient treatment. Considering the increase in life expectancy worldwide AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. A great amount of experimental and clinical evidence indicated that AD is a complex disorder characterized by widespread neurodegeneration of the CNS, with major involvement of the cholinergic system, causing progressive cognitive decline and dementia. The current treatment, based on the cholinergic hypothesis, is only symptomatic and mainly involves the restoration of acetylcholine (ACh) levels through the inhibition of acetylcholinesterase (AChE). Since the introduction of the Amaryllidaceae alkaloid galanthamine as an antidementia drug in 2001, alkaloids have been one of the most attractive groups for searching for new AD drugs. The present review aims to comprehensively summarize alkaloids of various origins as multi-target compounds for AD. From this point of view, the most promising compounds seem to be the β-carboline alkaloid harmine and several isoquinoline alkaloids since they can simultaneously inhibit several key enzymes of AD's pathophysiology. However, this topic remains open for further research on detailed mechanisms of action and the synthesis of potentially better semi-synthetic analogues.

• Keywords
• Alzheimer’s disease, marine alkaloids, multi-target compounds, plant alkaloids,
• MeSH
• Acetylcholinesterase MeSH
• Alkaloids * pharmacology   MeSH
• Alzheimer Disease * drug therapy   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Galantamine therapeutic use   MeSH
• Humans MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Alkaloids * MeSH
• Cholinesterase Inhibitors MeSH
• Galantamine MeSH

Tuberculosis (TB) is a widespread infectious disease caused by Mycobacterium tuberculosis. The increasing incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has created a need for new antiTB agents with new chemical scaffolds to combat the disease. Thus, the key question is: how to search for new antiTB and where to look for them? One of the possibilities is to search among natural products (NPs). In order to search for new antiTB drugs, the detailed phytochemical study of the whole Dicranostigma franchetianum plant was performed isolating wide spectrum of isoquinoline alkaloids (IAs). The chemical structures of the isolated alkaloids were determined by a combination of MS, HRMS, 1D, and 2D NMR techniques, and by comparison with literature data. Alkaloids were screened against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. avium, M. kansasii, and M. smegmatis). Alkaloids 3 and 5 showed moderate antimycobacterial activity against all tested strains (MICs 15.625-31.25 µg/mL). Furthermore, ten semisynthetic berberine (16a-16k) derivatives were developed and tested for antimycobacterial activity. In general, the derivatization of berberine was connected with a significant increase in antimycobacterial activity against all tested strains (MICs 0.39-7.81 μg/mL). Two derivatives (16e, 16k) were identified as compounds with micromolar MICs against M. tuberculosis H37Ra (MIC 2.96 and 2.78 µM). All compounds were also evaluated for their in vitro hepatotoxicity on a hepatocellular carcinoma cell line (HepG2), exerting lower cytotoxicity profile than their MIC values, thereby potentially reaching an effective concentration without revealing toxic side effects.

• Keywords
• Dicranostigma franchetianum, Papaveraceae, antimycobacterial activity, berberine, cytotoxicity, isoquinoline alkaloids,
• MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Berberine * pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis * MeSH
• Papaveraceae * MeSH
• Tuberculosis * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Berberine * MeSH

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease recognized as the most common form of dementia among elderly people. Due to the fact that the exact pathogenesis of AD still remains to be fully elucidated, the treatment is only symptomatic and available drugs are not able to modify AD progression. Considering the increase in life expectancy worldwide, AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. Due to their complex nitrogen-containing structures, alkaloids are considered to be promising candidates for use in the treatment of AD. Since the introduction of galanthamine as an antidementia drug in 2001, Amaryllidaceae alkaloids (AAs) and further isoquinoline alkaloids (IAs) have been one of the most studied groups of alkaloids. In the last few years, several compounds of new structure types have been isolated and evaluated for their biological activity connected with AD. The present review aims to comprehensively summarize recent progress on AAs and IAs since 2010 up to June 2021 as potential drugs for the treatment of AD.

• Keywords
• Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, docking study, isoquinoline alkaloids, monoaminooxidase, neuroprotective activity, prolyl oligopeptidase,
• MeSH
• Amaryllidaceae Alkaloids metabolism   MeSH
• Alzheimer Disease metabolism   MeSH
• Amaryllidaceae chemistry   MeSH
• Neurodegenerative Diseases metabolism   MeSH
• Prolyl Oligopeptidases metabolism   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Prolyl Oligopeptidases MeSH

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

• Keywords
• Alzheimer’s disease, amaryllidaceae alkaloid, butyrylcholinesterase, docking studies, norbelladine-type,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Amaryllidaceae Alkaloids chemistry   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Neuroblastoma drug therapy   pathology   MeSH
• Computer Simulation MeSH
• Cell Proliferation MeSH
• Molecular Docking Simulation * MeSH
• Tyramine analogs & derivatives   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Amaryllidaceae Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• norbelladine MeSH Browser
• Tyramine MeSH

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.

• Keywords
• 9-O-demethyllycorenine, Alzheimer’s disease, Amaryllidaceae, narciabduliine,
• MeSH
• Amaryllidaceae Alkaloids chemistry   pharmacology   MeSH
• Alkaloids chemistry   pharmacology   MeSH
• Alzheimer Disease MeSH
• Butyrylcholinesterase chemistry   ultrastructure   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Cholinesterases chemistry   ultrastructure   MeSH
• Circular Dichroism MeSH
• Catalytic Domain drug effects   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Cholinesterases MeSH

Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.

• Keywords
• Alzheimer’s disease, Amaryllidaceae, Narcissus pseudonarcissus cv. Carlton, alkaloids, butyrylcholinesterase, carltonine A–C, docking studies,
• MeSH
• Alkaloids chemistry   pharmacology   MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Humans MeSH
• Narcissus chemistry   MeSH
• Molecular Docking Simulation MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH

Bersavine is the new bisbenzylisoquinoline alkaloid isolated from the Berberis vulgaris L.(Berberidaceae) plant. The results of cytotoxicity screening 48 h post-treatment showed thatbersavine considerably inhibits the proliferation and viability of leukemic (Jurkat, MOLT-4), colon(HT-29), cervix (HeLa) and breast (MCF-7) cancer cells with IC50 values ranging from 8.1 to 11 μM.The viability and proliferation of leukemic Jurkat and MOLT-4 cells were decreased after bersavinetreatment in a time- and dose-dependent manner. Bersavine manifested concentration-dependentantiproliferative activity in human lung, breast, ovarian and hepatocellular carcinoma cell linesusing a xCELLigence assay. Significantly higher percentages of MOLT-4 cells exposed to bersavineat 20 μM for 24 h were arrested in the G1 phase of the cell cycle using the flow cytometry method.The higher percentage of apoptotic cells was measured after 24 h of bersavine treatment. Theupregulation of p53 phosphorylated on Ser392 was detected during the progression of MOLT-4 cellapoptosis. Mechanistically, bersavine-induced apoptosis is an effect of increased activity ofcaspases, while reduced proliferation seems dependent on increased Chk1 Ser345 phosphorylationand decreased Rb Ser807/811 phosphorylation in human leukemic cells.

• Keywords
• antiproliferative activity, apoptosis, bersavine, cell cycle, cytotoxicity,
• MeSH
• Alkaloids * chemistry   isolation & purification   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Berberis chemistry   MeSH
• Hep G2 Cells MeSH
• HT29 Cells MeSH
• Cytotoxins * chemistry   isolation & purification   pharmacology   MeSH
• Antineoplastic Agents, Phytogenic * chemistry   isolation & purification   pharmacology   MeSH
• G1 Phase drug effects   MeSH
• HeLa Cells MeSH
• Jurkat Cells MeSH
• Leukemia drug therapy   metabolism   pathology   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Drug Screening Assays, Antitumor MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkaloids * MeSH
• Cytotoxins * MeSH
• Antineoplastic Agents, Phytogenic * MeSH

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