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• Isoquinoline alkaloids were tested against cholinesterases in vitro and in silico. • N -norgalanthamine is the most active one inhibiting both cholinesterases. • 8-Hydroxy-9-methoxycrinine was a strong inhibitor of AChE. • (+)-9- O -demethylhomolycorine displayed a moderate BChE inhibition. • This is the first report on ChE inhibition by three off the tested alkaloids. All cholinesterase (ChE) inhibitory drugs in clinical use are nitrogenous compounds and among them, galanthamine as the latest anticholinesterase drug, contains a tetrahydroisoquinoline structure. For this reason, isoquinoline alkaloids seem to be attractive in search for novel drug candidates towards Alzheimer's disease (AD). Therefore, in the current work, we investigated inhibitory capacity of several alkaloids representing expanding group of biogenetically-related isoquinoline alkaloids from the Amaryllidaceae including lycorine, (+)-9- O -demethylhomolycorine, 6-hydroxybuphanisine, 9- O -demethoxymontanine, 3- epi- hydroxy-bulbispermine, tazettine, haemanthamine, (+)-haemanthidine, (-)-crinine, 8-hydroxy-9-methoxycrinine, and N -norgalanthamine against ChEs by microtiter enzyme inhibition assays. Our findings indicated that N -norgalanthamine is the most active one inhibiting both acetylcholinesterase (AChE, IC 50 = 2.42 ± 0.16 µg/mL) and butyrylcholinesterase (BChE, IC 50 = 20.87 ± 1.01 µg/mL) at 100 μg/mL, whereas IC 50 values of galanthamine used as the reference were 1.33 ± 0.11 µg/mL and 37.69 ± 2.93 µg/mL for AChE and BChE, respectively. Beside this, 8-hydroxy-9-methoxycrinine was a strong inhibitor of AChE (IC 50 = 6.92 ± 0.51 µg/mL), while (+)-9- O -demethylhomolycorine displayed a moderate BChE inhibition (IC 50 = 83.57 ± 1.36 µg/mL). Relevantly, 8-hydroxy-9-methoxycrinine and N -norgalanthamine were docked into active gorges of hAChE (PDB: 4EY6) and hBChE (PDB: 4TPK), which pointed out the detail that N -norgalanthamine displayed a very similar binding mode of to that of galanthamine. Moreover, both AChE-inhibiting alkaloids were found to stably bind to hAChE active site occupying the middle of the gorge between the catalytic site and the peripheral anionic site. 8-Hydroxy-9-methoxycrinine was also docked into the active site of BChE. We can conclude that among the tested alkaloids, N -norgalanthamine with dual ChE inhibitory effect seems to be the most promising anti-Alzheimer candidate molecule for future experiments. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 26 O-alkylcoumarins were synthesized and tested at 100 µM for their in vitro inhibitory potential against cholinesterases. • 12 of them exerted a potent and selective inhibition against BChE. • None of them possessed any potential to inhibit AChE. • MetaCore/MetaDrug analysis and docking simulations were applied the active compounds. Abstract Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC 50 = 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC 50 = 7.01 ± 0.28 µM – 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC 50 = 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC 50 = 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies. [ABSTRACT FROM AUTHOR]

Pteryxin is a dihydropyranocoumarin derivative found in Apiaceae family. In this study, pteryxin, which was previously isolated from the fruits of Mutellina purpurea , was investigated for its inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are the key enzymes in the pathology of Alzheimer's disease (AD). The compound was tested in vitro using ELISA microplate reader at 100 μg/ml and found to cause 9.30 ± 1.86% and 91.62 ± 1.53% inhibition against AChE and BChE, respectively. According to our results, pteryxin (IC 50 = 12.96 ± 0.70 μg/ml) was found to be a more active inhibitor of BChE than galanthamine (IC 50 = 22.16 ± 0.91 μg/ml; 81.93± 2.52% of inhibition at 100 μg/ml). Further study on pteryxin using molecular docking experiments revealed different possible binding modes with both polar and hydrophobic interactions inside the binding pocket of BChE. Top docking solution points out to the formation of two hydrogen bonds with the catalytic residues S198 and H438 of BChE as well as a strong π - π stacking with W231. Therefore, pteryxin as a natural coumarin seems to be a strong BChE inhibitor, which could be considered as a lead compound to develop novel BChE inhibitors for AD treatment. [ABSTRACT FROM AUTHOR]

The extracts from 25 plant species from Salvia , Hypericum , Onosma , Thymus , Origanum , Rosa , and Prunus with eight isolated compounds were screened for their memory-vitalizing potential against the enzymes, i.e., acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase (TYR) along with DPPH, DMPD, and NO radicals and iron-chelation capacity using spectrophotometric microtiter assays. The n -hexane:dichloromethane (1:1) extract of Onosma nigricaule roots (63.18 ± 0.56%) and the ethyl acetate extract of the aerial parts of Hypericum capitatum var. capitatum (50.79 ± 3.88%) were the most active toward AChE and BChE, respectively. The highest iron-chelating capacity was found in the n -hexane extract of Thymus sipyleus subsp. sipyleus var. sipyleus , where mostly Labiatae species exhibited better radical scavenging effect. Among the extracts, the roots of O. nigricaule , the aerial parts of Hypericum capitatum var. capitatum and T . sipyleus subsp. sipyleus var. sipyleus could be further evaluated for their memory-vitalizing properties based on different mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: In the current study, neuroprotective effect of the essential oil and aromatic waters of rose was investigated by in vitro and in silico methods. The samples were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Since oxidative damage is associated with neurodegeneration, antioxidant activity of the samples was determined by DPPH radical scavenging, metal-chelation, and ferric-reducing antioxidant power (FRAP) assays. Their chemical composition was elucidated by GC–MS. Anti-cholinesterase effects of the main components (citronellol, geraniol, nerol, and phenylethyl alcohol) were also examined. The rose oil showed a noteworthy inhibition against AChE (60.86±1.99%) and BChE (51.08±1.70%) at 1000μg/mL and low activity in DPPH radical scavenging and FRAP tests. Phenylethyl alcohol exerted higher cholinesterase inhibition than other components and applied further to molecular docking simulations. Docking and binding energies supporting experimental results show that the compound is more selective towards BChE than AChE. [Copyright &y& Elsevier]

Abstract: In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory and antioxidant activities of the aqueous and ethanol extracts of the leaves, ripe fruits, and unripe fruits of Juniperus communis ssp. nana, Juniperus oxycedrus ssp. oxycedrus, Juniperus sabina, Juniperus foetidissima, and Juniperus excelsa were investigated in the present study. Cholinesterase inhibition of the extracts was screened using ELISA microplate reader. Antioxidant activity of the extracts was tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging, ferrous ion-chelating, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. The extracts had low or no inhibition towards AChE, whereas the leaf aqueous extract of J. foetidissima showed the highest BChE inhibition (93.94±0.01%). The leaf extracts usually exerted higher antioxidant activity. We herein describe the first study on anticholinesterase and antioxidant activity by the methods of ferrous ion-chelating, superoxide radical scavenging, and ferric-reducing antioxidant power (FRAP) assays of the mentioned Juniperus species. [Copyright &y& Elsevier]

Based on our continuous effort to investigate chemistry and biology of the plant secondary metabolites, we were able to isolate a glycosidal flavonoid 1 from the Wild Egyptian Artichoke. The activity of dihydromyricetin 3-O-rhamnoside (sin. dihydromyricitrin, ampelopsin 3-O-rhamnoside) (1) against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE); its absolute configuration using X-ray crystallography were determined for the first time. Inhibitory activity of 1 against AChE and BChE enzymes were determined using a slightly modified version of Ellman's method. Compound 1 was revealed to have a potent inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 0.070 ± 0.008 and 0.071 ± 0.004 mM, respectively, where IC50 values of the reference drug (galanthamine) were 0.023 ± 0.15 and 0.047 ± 0.91 mM. Compound 1 could be a promising molecule against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: In the current study, in vitro neuroprotective effect of the ethyl acetate, methanol, and water extracts of Hypericum perforatum L. growing in Turkey was investigated through testing against acetylcholinesterase and butyrylcholinesterase at 50, 100, and 200μgmL−1, linked to Alzheimer''s disease, and tyrosinase at 250μgmL−1, related to Parkinson''s disease. As neurodegeneration is strongly correlated with oxidative damage and metal accumulation, antioxidant activity of the extracts was determined by radical scavenging assays against 2,2-diphenyl-1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylendiamine (DMPD), super oxide, and nitric oxide radicals, as well as metal-chelation capacity, ferric- (FRAP), and phosphomolibdenum-reducing antioxidant power (PRAP). Total phenol and flavonoid quantities of the extracts were also determined. The methanol extract showed the highest acetylcholinesterase inhibition (49.54±4.44%), while the ethyl acetate extract had the best inhibition towards butyrylcholinesterase (50.79±3.07%). Only the methanol extract showed low tyrosinase inhibition (19.21±1.44%). In the antioxidant assays, the methanol extract had a greater activity in general. [Copyright &y& Elsevier]

The dichloromethane (DCM), acetone, ethyl acetate and methanol extracts of the leaves and berries of Myrtus communis L. were screened against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase (TYRO), the enzymes linked to neurodegenerative diseases, at 200 μg ml− 1. Antioxidant activity was tested using radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and N, N- dimethyl- p-phenylenediamine (DMPD) radicals, metal chelation capacity, ferric-reducing antioxidant power (FRAP) and phosphomolybdenum-reducing antioxidant power (PRAP) assays. Total phenol and flavonoid quantification of the extracts was calculated spectrophotometrically. The extracts showed a moderate AChE (17.49 ± 3.99% to 43.15 ± 1.55%) and TYRO inhibition (4.48 ± 1.50% to 40.53 ± 0.47%). The leaf extracts were ineffective against BChE, while the berry extracts displayed inhibition between 21.83 ± 3.82% and 36.80 ± 2.00%. The polar extracts exerted remarkable scavenging effect against DPPH and DMPD and also in the FRAP assay, where the DCM extract of the berries had the best metal chelation capacity (79.29 ± 1.14%). This is the first study that demonstrates in vitro neuroprotective effects of myrtle. [ABSTRACT FROM AUTHOR]

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

Cholinesterase inhibition is one of the most treatment strategies against Alzheimer's disease (AD) where metal accumulation is also strongly associated with pathology of the disease. In the current study, we assessed inhibitory effect against acetyl- (AChE) and butyrylcholinesterase (BChE) and metal-chelating capacity of twelve diterpenes: arucadiol, miltirone, tanshinone IIa, 1-oxomiltirone, cryptotanshinone, 1,2-didehydromiltirone, 1,2-didehydrotanshinone IIa, 1β-hydroxycryptotanshinone, 15,16- dihydrotanshinone, tanshinone I, isotanshinone II, 1(S)-hydroxytanshinone IIa, and rosmarinic acid, isolated from Perovskia atriplicifolia and Salvia glutinosa. The compounds were tested at 10 μg/mL using ELISA microtiter assays against AChE and BChE. QSAR and molecular docking studies have been also performed on the active compounds. All of the compounds showed higher [e.g., IC50 = 1.12 ± 0.07 mg/mL for 1,2-didehydromiltirone, IC50 = 1.15 ± 0.07 mg/mL for cryptotanshinone, IC50 = 1.20 ± 0.03 μg/mL for arucadiol, etc.)] or closer [1,2-didehydrotanshinone IIa (IC50 = 5.98 ± 0.49 μg/mL) and 1(S)-hydroxytanshinone IIa (IC50 = 5.71 ± 0.27 μg/mL)] inhibition against BChE as compared to that of galanthamine (IC50 = 12.56 ± 0.37 μg/mL), whereas only 15,16-dihydrotanshinone moderately inhibited AChE (65.17 ± 1.39%). 1,2-Didehydrotanshinone IIa (48.94 ± 0.26%) and 1(S)-hydroxytanshinone IIa (47.18 ± 5.10%) possessed the highest metal-chelation capacity. The present study affords an evidence for the fact that selective BChE inhibitors should be further investigated as promising candidate molecules for AD therapy. [ABSTRACT FROM AUTHOR]

• Synthesis of S-benzyl dithiocarbamates derivatives via a single pot reaction setup. • Characterization of synthesized derivatives via NMR (1H and 13C), FT-IR and high resolution mass spectrometry. • In vitro enzyme inhibition assays against cholinesterase enzyme and monoamine oxidase. • Comprehensive in-silico investigations of synthesized derivatives. The current study was aimed to identify the selective and multi-targeted inhibitors of cholinesterase and monoamine oxidase enzymes. For this purpose, a novel class of multi-targeted compounds i.e., S -benzyl dithiocarbamates (1-30) was synthesized via a single pot reaction and the structures were characterized via NMR (1H and 13C), FT-IR and high-resolution mass spectrometry (HRMS). Moreover, the purity of the final products was determined using thin-layer chromatography (TLC). The compounds were evaluated for their inhibitory potential against cholinesterases (ChE) and monoamine oxidases (MAO). Among all derivatives, compound 5 (2-(trifluoromethyl) benzyl azepane-1-carbodithioate) depicted the maximum inhibition of AChE and BChE enzyme with an IC 50 value of 4.37±0.94 and 14.9±1.11, respectively. The derivative 11, expressed maximum inhibition of MAO-A and MAO-B with an IC 50 value of 1.14±0.03 and 1.01 ± 0.16 µM, respectively. Whereas, compound 16 exhibited maximum inhibitory potential against all four targeted enzymes i.e., AChE, BChE, MAO-A and MAO-B with an IC 50 value of 1.39±0.07 µg/ mL, 1.52±0.14 µg/ mL, 44.9±1.54 µM and 2.85±0.21 µM, respectively. The chemical reactivity profile of the potent derivatives were evaluated through density functional theory studies (DFT) where it was found that compound 5, 6 and 11 possessed reactive character due to narrow LUMO/HOMO energy gap. In addition, Molecular docking studies revealed excellent docking scores and produced sable protein-ligand complexes. The stability of protein-ligand complex was affirmed by molecular dynamic simulations which revealed stable and equilibrated trajectories of simulated complexes. The findings of in-vitro and in-silico studies suggested compound 16 as a promising multi-targeted compound that can be act as lead molecule for the treatment of AD. [Display omitted] [ABSTRACT FROM AUTHOR]

• Annual phytochemical profile of 5 Origanum species was established. • Cholinesterase inhibition and antioxidant effects of 60 extracts were tested. • The links between the phytochemical fingerprints and activities were revealed. • Aromadendrin showed good correlation with AChE, BChE, and FRAP activities. • Caffeoylarbutin had the lowest binding energy against both enzymes. The ethanol extracts of five Origanum species : O. majorana L., O. onites L., O. syriacum L., O. vulgare subsp. hirtum (Link) Ietsw., and O. vulgare subsp. viride (Boiss.) Hayek, collected annually (each month), were investigated for their cholinesterase inhibition and antioxidant effects. The phytochemical composition of a total of 60 extracts was assessed by HPLC-DAD-ESI/HRMS, revealing the presence of a total of 73 compounds. Possible correlation between the bioactivity and metabolite profiles during 12 months was monitored. Acetylcholinesterase (AChE) inhibitory activity was found to be the highest between April and November (50.29–75.95%, 200 μg/mL), while the highest inhibition towards butyrylcholinesterase (BChE) was observed for the extracts between April and October (71.68–88.97%). Aromadendrin showed good correlation with anti-AChE, anti-BChE and reducing power activities. Furthermore, molecular docking data with aromadendrin, caffeoylarbutin and eriodictyol indicated that caffeoylarbutin had the lowest binding energy against both enzymes. [ABSTRACT FROM AUTHOR]

• Novel [3-substitue-6-oxopyridazin-1(6 H)-yl]methyl carbamate derivatives were synthesized. • Compounds 7c , 14c , and 16c showed significant inhibitory activity against eqBuChE. • Compound 7c displayed a competitive inhibition while 14c and 16c showed a mixed-type inhibition. • Molecular docking study was performed for the selected compounds. In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (Ee AChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl heptylcarbamate (16c , eqBuChE, IC 50 = 12.8 μM; Ee AChE, no inhibition at 100 μM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC 50 = 3.25 μM; Ee AChE, IC 50 = 0.11 μM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC 50 = 35 μM; Ee AChE, no inhibition at 100 μM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC 50 = 34.5 μM; Ee AChE, 38.9% inhibition at 100 μM) was the most active derivative against Ee AChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2 H)-one scaffold is important for the inhibitory activity and compounds 7c , 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer's disease treatment. [ABSTRACT FROM AUTHOR]