Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. CNS Neurol Disord Drug Targets. 2024;23(6):773-783. doi: 
10.2174/1871527322666230417083053.

Cholinesterase Inhibitory and In Silico Toxicity Assessment of Thirty-Four 
Isoquinoline Alkaloids - Berberine as the Lead Compound.

Senol Deniz FS(1), Ekhteiari Salmas R(2), Emerce E(3), Sener B(1), Orhan 
IE(1)(4).

Author information:
(1)Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara 
06330, Türkiye.
(2)Department of Chemistry, Britannia House, King's College London, UK.
(3)Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Gazi 
University, Ankara 06330, Türkiye.
(4)Turkish Academy of Sciences (TÜBA), Vedat Dalokay Street, No. 112, Ankara 
06670, Türkiye.

BACKGROUND: Cholinesterase (ChE) inhibitors used currently in clinics for the 
treatment of Alzheimer's disease (AD) are the most prescribed drug class with 
nitrogen-containing chemical formula. Galanthamine, the latest generation 
anti-ChE drug, contains an isoquinoline structure.
OBJECTIVE: The aim of the current study was to investigate the inhibitory 
potential of thirty-four isoquinoline alkaloids, e.g. (-)-adlumidine, 
β-allocryptopine, berberine, (+)-bicuculline, (-)-bicuculline, (+)-bulbocapnine, 
(-)-canadine, (±)-chelidimerine, corydaldine, (±)-corydalidzine, 
(-)-corydalmine, (+)-cularicine, dehydrocavidine, (+)-fumariline, 
(-)-fumarophycine, (+)-α-hydrastine, (+)-isoboldine, 13-methylcolumbamine, 
(-)-norjuziphine, norsanguinarine, (-)-ophiocarpine, (-)-ophiocarpine-Noxide, 
oxocularine, oxosarcocapnine, palmatine, (+)-parfumine, protopine, 
(+)-reticuline, sanguinarine, (+)-scoulerine, (±)-sibiricine, (±)-sibiricine 
acetate, (-)-sinactine, and (-)-stylopine isolated from several Fumaria 
(fumitory) and Corydalis species towards acetyl- (AChE) and 
butyrylcholinesterase (BChE) by microtiter plate assays. The alkaloids with 
strong ChE inhibition were proceeded to molecular docking simulations as well as 
in silico toxicity screening for their mutagenic capacity through VEGA QSAR 
(AMES test) consensus model and VEGA platform as statistical approaches. The 
inputs were evaluated in a simplified molecular input-line entry system 
(SMILES).
METHODS: ChE inhibition assays indicated that the highest AChE inhibition was 
caused by berberine (IC50: 0.72 ± 0.04 μg/mL), palmatine (IC50: 6.29 ± 0.61 
μg/mL), β-allocryptopine (IC50: 10.62 ± 0.45 μg/mL), (-)-sinactine (IC50: 11.94 
± 0.44 μg/mL), and dehydrocavidine (IC50: 15.01 ± 1.87 μg/mL) as compared to 
that of galanthamine (IC50: 0.74 ± 0.01 μg/mL), the reference drug with 
isoquinoline skeleton. Less number of the tested alkaloids exhibited notable 
BChE inhibition. Among them, berberine (IC50: 7.67 ± 0.36 μg/mL) and 
(-)-corydalmine (IC50: 7.78 ± 0.38 μg/mL) displayed a stronger inhibition than 
that of galanthamine (IC50: 12.02 ± 0.25 μg/mL). The mutagenic activity was 
shown for β-allocryptopine, (+)- and (-)-bicuculline, (±)-corydalidzine, 
(-)-corydalmine, (+)-cularicine, (-)- fumarophycine, (-)-norjuziphine, 
(-)-ophiocarpine-N-oxide, (+)-scoulerine, (-)-sinactine, and (-)- stylopine by 
means of in silico experiments.
RESULTS: The results obtained by molecular docking simulations of berberine, 
palmatine, and (-)- corydalmine suggested that the estimated free ligand-binding 
energies of these compounds inside the binding domains of their targets are 
reasonable to make them capable of establishing strong polar and nonpolar bonds 
with the atoms of the active site amino acids.
CONCLUSION: Our findings revealed that berberine, palmatin, and (-)-corydalmine 
stand out as the most promising isoquinoline alkaloids in terms of ChE 
inhibition. Among them, berberine has displayed a robust dual inhibition against 
both ChEs and could be evaluated further as a lead compound for AD.

Copyright© Bentham Science Publishers; For any queries, please email at 
epub@benthamscience.net.

DOI: 10.2174/1871527322666230417083053
PMID: 37073143 [Indexed for MEDLINE]


2. Toxins (Basel). 2022 Jul 15;14(7):491. doi: 10.3390/toxins14070491.

Can Isoquinoline Alkaloids Affect Platelet Aggregation in Whole Human Blood?

Parvin MS(1), Hrubša M(2), Fadraersada J(2), Carazo A(2), Karlíčková J(1), 
Cahlíková L(1), Chlebek J(1), Macáková K(1), Mladěnka P(2).

Author information:
(1)The Department of Pharmacognosy and Pharmaceutical Botany, Faculty of 
Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech 
Republic.
(2)The Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec 
Králové, Charles University, 500 05 Hradec Králové, Czech Republic.

Isoquinoline alkaloids have multiple biological activities, which might be 
associated with positive pharmacological effects as well as negative adverse 
reactions. As bleeding was suggested to be a side effect of the isoquinoline 
alkaloid berberine, we decided to ascertain if different isoquinoline alkaloids 
could influence hemocoagulation through the inhibition of either platelet 
aggregation or blood coagulation. Initially, a total of 14 compounds were 
screened for antiplatelet activity in whole human blood by impedance 
aggregometry. Eight of them demonstrated an antiplatelet effect against 
arachidonic acid-induced aggregation. Papaverine and bulbocapnine were the most 
potent compounds with biologically relevant IC50 values of 26.9 ± 12.2 μM and 
30.7 ± 5.4 μM, respectively. Further testing with the same approach confirmed 
their antiplatelet effects by employing the most physiologically relevant 
inducer of platelet aggregation, collagen, and demonstrated that bulbocapnine 
acted at the level of thromboxane receptors. None of the alkaloids tested had an 
effect on blood coagulation measured by a mechanical coagulometer. In 
conclusion, the observed antiplatelet effects of isoquinoline alkaloids were 
found mostly at quite high concentrations, which means that their clinical 
impact is most likely low. Bulbocapnine was an exception. It proved to be a 
promising antiplatelet molecule, which may have biologically relevant effects.

DOI: 10.3390/toxins14070491
PMCID: PMC9324755
PMID: 35878229 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


3. Pharmacol Res. 2022 Mar;177:106126. doi: 10.1016/j.phrs.2022.106126. Epub 2022
 Feb 10.

Natural isoquinoline alkaloids: Pharmacological features and multi-target 
potential for complex diseases.

Plazas E(1), Avila M MC(2), Muñoz DR(3), Cuca S LE(4).

Author information:
(1)Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, 
Departamento de Química, Grupo de Investigación en Productos Naturales Vegetales 
Bioactivos, Av Cr 30. #45-03, 111321 Bogotá, Colombia. Electronic address: 
eaplazasg@unal.edu.co.
(2)Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, 
Departamento de Química, Grupo de Investigación en Productos Naturales Vegetales 
Bioactivos, Av Cr 30. #45-03, 111321 Bogotá, Colombia.
(3)Universidad de Ciencias Aplicadas y Ambientales, Facultad de Ciencias, Bogotá 
111166, Colombia.
(4)Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, 
Departamento de Química, Grupo de Investigación en Productos Naturales Vegetales 
Bioactivos, Av Cr 30. #45-03, 111321 Bogotá, Colombia. Electronic address: 
lecucas@unal.edu.co.

Complex diseases such as neurodegenerative disorders and cancer constitute a 
growing public health problem due to the rising incidence and lack in effective 
therapies. 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 drug candidates. Plant-derived 
isoquinoline alkaloids comprise a vast source of multimodal agents with unique 
structural diversity, and variated range of pharmacological activities. This 
review offers an exhaustive compilation of the pharmacological relevance and 
multi-target potential of natural isoquinolines, emphasizing their features and 
promising activity in complex diseases such as Alzheimer, Parkinson, and Cancer. 
Selected examples were discussed in depth to illustrate the most relevant 
structural motifs and their possible relationship with the multimodal activity 
offering a comprehensive baseline in the search and optimization of isoquinoline 
scaffolds with polypharmacological potential for complex diseases.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.phrs.2022.106126
PMID: 35151857 [Indexed for MEDLINE]


4. Pharmaceutics. 2021 Oct 3;13(10):1611. doi: 10.3390/pharmaceutics13101611.

Identification of Effective Anticancer G-Quadruplex-Targeting Chemotypes through 
the Exploration of a High Diversity Library of Natural Compounds.

Platella C(1), Ghirga F(2), Zizza P(3), Pompili L(3), Marzano S(4), Pagano B(4), 
Quaglio D(2), Vergine V(2), Cammarone S(2), Botta B(2), Biroccio A(3), Mori 
M(5), Montesarchio D(1).

Author information:
(1)Department of Chemical Sciences, University of Naples Federico II (Complesso 
Universitario di Monte S. Angelo), Via Cintia, 21, 80126 Napoli, Italy.
(2)Department of Chemistry and Technology of Drugs, "Department of Excellence 
2018-2022", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
(3)Oncogenomic and Epigenetic Unit, IRCCS-Regina Elena National Cancer 
Institute, Via Elio Chianesi 53, 00144 Rome, Italy.
(4)Department of Pharmacy, "Department of Excellence 2018-2022", University of 
Naples Federico II, Via D.Montesano, 49, 80131 Napoli, Italy.
(5)Department of Biotechnology, Chemistry and Pharmacy, "Department of 
Excellence 2018-2022", University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural 
compounds have been thus far poorly explored, though representing appealing 
candidates due to the high structural diversity of their scaffolds. In this 
regard, a unique high diversity in-house library composed of ca. one thousand 
individual natural products was investigated. The combination of molecular 
docking-based virtual screening and the G4-CPG experimental screening assay 
proved to be useful to quickly and effectively identify-out of many natural 
compounds-five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, 
Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously 
demonstrated the selective interaction of these compounds with G4s compared to 
duplex DNA. The rationale behind the G4 selective recognition was suggested by 
molecular dynamics simulations. Indeed, the selected ligands proved to 
specifically interact with G4 structures due to peculiar interaction patterns, 
while they were unable to firmly bind to a DNA duplex. From biological assays, 
Chelidonine and Rotenone emerged as the most active compounds of the series 
against cancer cells, also showing good selectivity over normal cells. Notably, 
the anticancer activity correlated well with the ability of the two compounds to 
target telomeric G4s.

DOI: 10.3390/pharmaceutics13101611
PMCID: PMC8537501
PMID: 34683905

Conflict of interest statement: The authors declare no conflict of interest.


5. Phytochemistry. 2018 May;149:123-131. doi: 10.1016/j.phytochem.2017.12.023.
Epub  2018 Feb 27.

An OMIC approach to elaborate the antibacterial mechanisms of different 
alkaloids.

Avci FG(1), Sayar NA(2), Sariyar Akbulut B(3).

Author information:
(1)Department of Bioengineering, Marmara University, 34722, Kadikoy, Istanbul, 
Turkey; Department of Bioengineering, Adana Science and Technology University, 
01250, Adana, Turkey. Electronic address: gizemavci@gmail.com.
(2)Department of Bioengineering, Marmara University, 34722, Kadikoy, Istanbul, 
Turkey. Electronic address: alpagu.sayar@marmara.edu.tr.
(3)Department of Bioengineering, Marmara University, 34722, Kadikoy, Istanbul, 
Turkey. Electronic address: berna.akbulut@marmara.edu.tr.

Plant-derived substances have regained interest in the fight against antibiotic 
resistance owing to their distinct antimicrobial mechanisms and multi-target 
properties. With the recent advances in instrumentation and analysis techniques, 
OMIC approaches are extensively used for target identification and elucidation 
of the mechanism of phytochemicals in drug discovery. In the current study, RNA 
sequencing based transcriptional profiling together with global differential 
protein expression analysis was used to comparatively elaborate the activities 
and the effects of the plant alkaloids boldine, bulbocapnine, and roemerine 
along with the well-known antimicrobial alkaloid berberine in Bacillus subtilis 
cells. The transcriptomic findings were validated by qPCR. Images from scanning 
electron microscope were obtained to visualize the effects on the whole-cells. 
The results showed that among the three selected alkaloids, only roemerine 
possessed antibacterial activity. Unlike berberine, which is susceptible to 
efflux through multidrug resistance pumps, roemerine accumulated in the cells. 
This in turn resulted in oxidative stress and building up of reactive oxygen 
species, which eventually deregulated various pathways such as iron uptake. 
Treatment with boldine or bulbocapnine slightly affected various metabolic 
pathways but has not changed the growth patterns at all.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.phytochem.2017.12.023
PMID: 29494814 [Indexed for MEDLINE]