Narciindole A, the first representative of Amaryllidaceae alkaloids with an indol-3-ylmethanone framework, was isolated from bulbs of Narcissus pseudonarcissus (L.) cv. Carlton, together with carltonine D and carltonine E, which share the same unusual structural motif as dimeric carltonine C (reported in 2020), exhibiting atropisomerism. Unambiguous structure elucidations have been achieved by NMR spectroscopy, HRMS, and comparison with literature data of related alkaloids. Furthermore, the chirality of known alkaloids with a galanthindole biaryl core was revised using optical rotation. Last, but not least, a biosynthetic pathway for dimeric carltonine-type alkaloids was proposed. Unfortunately, in terms of biological activity, the isolated alkaloids showed only moderate inhibition of human acetylcholinesterase and/or butyrylcholinesterase.
- Klíčová slova
- Alkaloids, Alzheimer's disease, Amaryllidaceae, Atropisomerism, Carltonines, Narcissus pseudonarcissus (L.) cv. Carlton, Specific rotation revised, Structure elucidation,
- Publikační typ
- časopisecké články MeSH
Polycyclic compounds with N-methyl substitution, structurally related to Amaryllidaceae alkaloids, have been synthesised, together with their analogues bearing a quaternary nitrogen atom. To prevent the lone electron pair of the nitrogen from interfering with the reaction sequence, two approaches to the synthesis were investigated: N-oxidation and Boc protection of the nitrogen. The second method was more successful due to the limited stability of N-oxides in the halocyclisation step. An asymmetric version of the synthesis was also developed for this type of compounds. The prepared products were tested in vitro for their cholinesterase inhibitory activity and the results were rationalised by molecular docking studies with human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). In general, our products were more active against BuChE than against AChE, and it was noted that larger ligands should be prepared for future studies, since in some cases acetylcholine can still fit into the active site along with the bound ligand.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- alkaloidy amarylkovitých * chemie farmakologie MeSH
- alkaloidy * chemie MeSH
- Amaryllidaceae * chemie metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie MeSH
- dusík MeSH
- lidé MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- alkaloidy amarylkovitých * MeSH
- alkaloidy * MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- dusík MeSH
One undescribed indole alkaloid together with twenty-two known compounds have been isolated from aerial parts of Vinca minor L. (Apocynaceae). 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. The NMR data of several alkaloids have been revised, corrected, and missing data have been supplemented. Alkaloids isolated in sufficient quantity were screened for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BuChE; E.C. 3.1.1.8) inhibitory activity. Selected compounds were also evaluated for prolyl oligopeptidase (POP; E.C. 3.4.21.26), and glycogen synthase 3β-kinase (GSK-3β; E.C. 2.7.11.26) inhibition potential. Significant hBuChE inhibition activity has been shown by (-)-2-ethyl-3[2-(3-ethylpiperidinyl)-ethyl]-1H-indole with an IC50 value of 0.65 ± 0.16 μM. This compound was further studied by enzyme kinetics, along with in silico techniques, to reveal the mode of inhibition. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion.
- Klíčová slova
- (−)-2-ethyl-3[2-(3-ethylpiperidinyl)-ethyl]-1H-indole, Alkaloids, Alzheimer's disease, Apocynaceae, Butyrylcholinesterase, Docking studies, Vinca minor, Vincaminorudeine,
- MeSH
- acetylcholinesterasa MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- butyrylcholinesterasa MeSH
- fytonutrienty farmakologie MeSH
- indolové alkaloidy farmakologie MeSH
- kinasa glykogensynthasy 3beta MeSH
- monoterpeny farmakologie MeSH
- nadzemní části rostlin chemie MeSH
- Vinca * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- butyrylcholinesterasa MeSH
- fytonutrienty MeSH
- indolové alkaloidy MeSH
- kinasa glykogensynthasy 3beta MeSH
- monoterpeny MeSH
Alzheimeŕs disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.
- Klíčová slova
- Acetylcholinesterase, Alzheimeŕs disease, Amaryllidaceae alkaloid, Butyrylcholinesterase, Docking studies, Montanine-type,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- alkaloidy chemická syntéza chemie farmakologie MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- isochinoliny chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- alkaloidy MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- isochinoliny MeSH
- montanine MeSH Prohlížeč
The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.
- Klíčová slova
- 3-O-methylpancracine, Amaryllidaceae, analogues, antimycobacterial activity, cytotoxicity, galanthamine, tuberculosis,
- MeSH
- alkaloidy amarylkovitých škodlivé účinky chemická syntéza farmakologie MeSH
- antibakteriální látky škodlivé účinky chemická syntéza farmakologie MeSH
- buňky Hep G2 MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkaloidy amarylkovitých MeSH
- antibakteriální látky 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.
- Klíčová slova
- Alzheimer’s disease, amaryllidaceae alkaloid, butyrylcholinesterase, docking studies, norbelladine-type,
- MeSH
- acetylcholinesterasa chemie MeSH
- alkaloidy amarylkovitých chemie MeSH
- butyrylcholinesterasa chemie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- lidé MeSH
- nádorové buňky kultivované MeSH
- neuroblastom farmakoterapie patologie MeSH
- počítačová simulace MeSH
- proliferace buněk MeSH
- simulace molekulového dockingu * MeSH
- tyramin analogy a deriváty chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- alkaloidy amarylkovitých MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- norbelladine MeSH Prohlížeč
- tyramin 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.
- Klíčová slova
- 9-O-demethyllycorenine, Alzheimer’s disease, Amaryllidaceae, narciabduliine,
- MeSH
- alkaloidy amarylkovitých chemie farmakologie MeSH
- alkaloidy chemie farmakologie MeSH
- Alzheimerova nemoc MeSH
- butyrylcholinesterasa chemie ultrastruktura MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- cholinesterasy chemie ultrastruktura MeSH
- cirkulární dichroismus MeSH
- katalytická doména účinky léků MeSH
- lidé MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkaloidy amarylkovitých MeSH
- alkaloidy MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- cholinesterasy MeSH
Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity 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 AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC50 values of 18.7 ± 2.3 µM and 1.34 ± 0.31 µM, respectively. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.
- Klíčová slova
- Alkaloids, Alzheimer's disease, Amaryllidaceae, Docking studies, Narcieliine, Zephyranthes citrina,
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- alkaloidy chemie izolace a purifikace farmakologie terapeutické užití MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- Amaryllidaceae chemie metabolismus MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemie metabolismus farmakologie terapeutické užití MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- katalytická doména MeSH
- kinetika MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární konformace MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- alkaloidy MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC50value of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC50 value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds.
- Klíčová slova
- Acetylcholinesterase, Alzheimer’s disease, Amaryllidaceae, Butyrylcholinesterase, Docking studies, Haemanthamine,
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- alkaloidy amarylkovitých chemie metabolismus terapeutické užití MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- Amaryllidaceae chemie metabolismus MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza metabolismus terapeutické užití MeSH
- estery chemie MeSH
- fenantridiny chemie metabolismus terapeutické užití MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- kinetika MeSH
- lidé MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- alkaloidy amarylkovitých MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- estery MeSH
- fenantridiny MeSH
- hemanthamine MeSH Prohlížeč
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.
- Klíčová slova
- Alzheimer’s disease, Amaryllidaceae, Narcissus pseudonarcissus cv. Carlton, alkaloids, butyrylcholinesterase, carltonine A–C, docking studies,
- MeSH
- alkaloidy chemie farmakologie MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- lidé MeSH
- Narcissus chemie MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alkaloidy MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
