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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]

Context:Xeranthemum annuumL. (Asteraceae) (XA) is an ornamental and medicinal species with limited bioactivity and phytochemical data. Objective:Identification of anticholinesterase, antioxidant, anti-inflammatory and analgesic effects of the flower and root–stem (R-S) extracts of XA. Materials and methods:Anticholinesterase (at 100 μg mL−1) and antioxidant (at 1000 μg mL−1) effects of various extracts were evaluated via microtiter assays, while anti-inflammatory and analgesic effects of the R-S extracts were tested using carrageenan-induced hind paw oedema (100 and 200 mg kg−1) andp-benzoquinone (PBQ) writhing models (200 mg kg−1) in male Swiss albino mice. The R-S ethanol extract of XA was subjected to isolation studies using conventional chromatographic methods. Results:Most of the extracts showed inhibition over 85% against butyrylcholinesterase and no inhibition towards acetylcholinesterase. The flower chloroform and the R-S ethyl acetate extracts were most effective (97.85 ± 0.94% and 96.89 ± 1.09%, respectively). The R-S ethanol extract displayed a remarkable scavenging activity against DPPH (77.33 ± 1.99%) and in FRAP assay, while the hexane extract of the R-S parts possessed the highest metal-chelating capacity (72.79 ± 0.33%). The chloroform extract of the R-S caused a significant analgesic effect (24.4%) in PBQ writhing model. No anti-inflammatory effect was observed. Isolation of zierin and zierin xyloside, which were inactive in anticholinesterase assays, was achieved from the R-S ethanol extract. Discussion and conclusion:This is the first report of anticholinesterase, antioxidant, analgesic and anti-inflammatory activities and isolation of zierin and zierin xyloside from XA. Therefore, XA seems to contain antioxidant and BChE-inhibiting compounds. [ABSTRACT FROM AUTHOR]

Coumarins are widely distributed, plant-derived, 2 H -1-benzopyran-2-one derivatives which have attracted intense interest in recent years as a result of their diverse and potent pharmacological properties. Particularly, their effects on the central nervous system (CNS) have been established. The present review discusses the most important pharmacological effects of natural and synthetic coumarins on the CNS, including their interactions with benzodiazepine receptors, their dopaminergic and serotonergic affinity, and their ability to inhibit cholinesterases and monoamine oxidases. The structure-activity relationships pertaining to these effects are also discussed. This review posits that natural or synthetic coumarins have the potential for development in the therapy of psychiatric and neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, schizophrenia, anxiety, epilepsy, and depression. [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 this study, cholinesterase inhibitory potential relevant to Alzheimer''s disease and antioxidant activities of the dichloromethane, ethyl acetate, and ethanol extracts from the aerial parts and/or roots of fourteen Salvia (sage) species (S. argentea, S. bracteata, S. caespitosa, S. cryptantha, S. glutinosa, S. indica, S. microstegia, S. multicaulis, S. pinnata, S. quezelii, S. syriaca, S. tobeyi, S. verticillata subsp. amasiaca, and S. viscosa) were investigated. Cholinesterase inhibition was determined by Ellman method at 25, 50, and 100μgml−1. Their antioxidant activity was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, metal-chelation capacity, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were also determined. The dichloromethane and ethanol extracts of the aerial parts of S. cryptantha were the most active ones against AChE (56.22±1.07%) and BChE (33.80±4.18%), respectively. The ethanol extracts exhibited better scavenging activity and FRAP. Anticholinesterase activity of 9 Salvia species (S. argentea, S. bracteata, S. caespitosa, S. indica, S. pinnata, S. quezelii, S. syriaca, S. tobeyi, and S. viscosa) is reported for the first time in the current study. [Copyright &y& Elsevier]

The extracts of various marine sponges (Agelas oroides and Axinella damicornis, Axinella cannabina, Ircinia spinulosa, I. fasciculata, and I. variabilis, Dysidea avara, and Sarcotragus spinulosus) collected from different spots of the Turkish cost of the Mediterranean Sea have been evaluated for their antibacterial, antifungal, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, and acetylcholinesterase (AChE) inhibitory activities. Three compounds (oroidin, 4,5-dibromopyrrol-2-carboxylic acid, and 25-hydroxy-24-methylcholesterol) were isolated from A. oroides and tested in the same manner. The sponge extracts showed notable antimicrobial and anti-AChE activity and low DPPH scavenging activity. Oroidin was found to have moderate anti-AChE and strong radical scavenging activities. The results demonstrated that the sponge extracts exerted a variable degree of antibacterial, anti-radical, and anti-AChE activity, whereas they seemed to have similar antifungal effect. Our findings point out to the fact that the collection site has an important influence on bioactivity of the sponges. [ABSTRACT FROM AUTHOR]

Abstract: In the current study, the n-hexane, chloroform, ethyl acetate, water, and n-butanol fractions obtained from the main ethanol extract of Cistus laurifolius L. were evaluated for their cholinesterase inhibitory effects against acetyl- (AChE) and butyrylcholinesterase (BChE), at 50, 100, and 200μg/ml, using an ELISA microplate reader. The antioxidative effect of the extract and fractions was also determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferrous ion-chelation capacity, and ferric-reducing antioxidant power (FRAP) test systems. Total phenol and flavonoid contents of the extract and fractions were calculated using Folin-Ciocalteau and aluminium chloride reagents. Three flavonoid derivatives; 3-O-methylquercetin (1), 3,7-O-dimethylquercetin (2), and 3,7-O-dimethylkaempferol (3) isolated from the CHCl3 fraction were also tested in the same manner. Our experimental findings indicated that the ethanol extract exerted the highest AChE inhibition (80.07±1.06% at 200μg/ml). The ethyl acetate and n-butanol fractions displayed the best activity against DPPH and FRAP assays. [Copyright &y& Elsevier]

Several extracts of the leaves and fruits of Juglans regia L. were assessed for their neuroprotective effects through antioxidant and anti-cholinesterase methods. Anticholinesterase activity was determined against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes vital for Alzheimer's disease, at 50, 100 and 200 μg ml− 1. Antioxidant activity was tested using radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), N, N-dimethyl- p-phenylenediamine (DMPD), superoxide (SO), nitric oxide (NO) and hydrogen peroxide (H2O2) radicals, as well as ferric ion-chelating capacity, ferric- and phosphomolybdenum-reducing antioxidant power at 500, 1000 and 2000 μg ml− 1. Total phenol and flavonoid quantification of the extracts was calculated. The extracts scavenged DPPH radical in varying degrees; however, they did not scavenge DPMD and H2O2. Only the dichloromethane and water extracts were able to quench SO (10.09 ± 1.38%) and NO (24.09 ± 2.19%) radicals, respectively, at low level. The extracts showed either low or no BChE inhibition and no AChE inhibition. [ABSTRACT FROM AUTHOR]

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]

Abstract: Dichloromethane, ethyl acetate, acetone, methanol, and water extracts prepared from the fruits and leaves of Laurocerasus officinalis Roem. (LO) (Rosaceae) were screened for their cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the key enzymes in pathogenesis of Alzheimer''s disease (AD), using ELISA microplate reader at 50, 100, and 200μgmL−1. As AD is associated with oxidative stress, the antioxidant activity of the extracts was also tested by radical-forming methods against 2,2-diphenyl-1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylendiamine (DMPD), and superoxide radicals as well as iron-related methods; iron-chelating capacity and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid quantification was achieved using Folin–Ciocalteau and AlCl3 reagents, respectively. The highest AChE (44.01±1.75%) and BChE (19.91±0.37%) inhibition was caused by the LO-leaf-methanol extract 200μgmL−1, while it showed the best radical-scavenging activity against DPPH at 2000μgmL−1. Only, the dichloromethane and water extracts of the fruits and the leaf water extract had an iron-chelating capacity, while the leaf methanol extract displayed the highest FRAP. The leaf methanol extract (113.45±0.71mgg−1 extract) was found to be the richest in total phenols, while the leaf acetone extract (139.90±4.64mgg−1 extract) had the most abundant amount of total flavonoids. [Copyright &y& Elsevier]

The EtOH extracts of the leaves of two new cultivars (Uysal-SFU and Turgut-SFT) of Salvia fruticosa Mill. was tested against acetylcholinesterase (IC50: 30.62 ± 3.27 and 32.97 ± 2.33 µg/mL for SFU and SFT, respectively) and butyrylcholinesterase (IC50: 69.91 ± 1.08 µg/mL and 86.55 ± 1.26 µg/mL), respectively, relevant to Alzheimer's disease. The essential oils showed a stumpy inhibition against AChE and no inhibition against BChE. DPPH radical scavenging activity of the extracts (86.70 ± 0.17% and 86.14 ± 1.13% for SFU and SFT, respectively) was stronger than that of quercetin (85.51 ± 0.17%): Their (1.24 ± 0.05 and 1.04 ± 0.16 for SFU and SFT, respectively) ferric-reducing antioxidant power were close to that of the reference (e.g. quercetin, 1.42 ± 0.14). Molecular docking simulations were performed on their major monoterpenes. Our findings revealed that the leaf EtOH extracts of two cultivars are promising inhibitors of both AChE and BChE. [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]

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]

The ethanol (EtOH) extracts of thirty-four taxa from the Amelanchier , Cotoneaster , Pyrus , and Sorbus genera (Rosaceae) have been screened for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at 200 μg/mL as well as their antioxidant activity using metal-chelating capacity, ferric-reducing antioxidant power (FRAP), and N , N -dimethyl- p -phenylenediamine (DMPD) radical scavenging activity at 2000 μg/mL using ELISA microtiter assays. Our results indicated that two extracts of Sorbus umbelleta from different localities had 56.20 ± 5.05% (IC 50 = 182.1 μg/mL) and 58.18 ± 3.77% (IC 50 = 177.8 μg/mL) of inhibition against AChE, while 50.67 ± 0.32% of BChE inhibition (IC 50 = 206.5 μg/mL) was caused by the extract of Cotoneaster meyeri . Among the tested extracts, S. subfusca displayed the highest FRAP value (1.618 ± 0.09) and DMPD radical scavenging activity (31.05 ± 0.01%), while the best metal-chelating capacity (27.13 ± 2.01%) was found to belong to the extract of Sorbus kusnetzovii . The EtOH extracts of the active species ( e.g. Cotoneaster meyeri , two samples of Sorbus umbelleta , and Sorbus subfusca ) in enzyme inhibition assays have also been subjected to HPLC analysis to quantify some selected phenolic acids and flavonoid derivatives. Chlorogenic acid (28.83 ± 0.67–149.10 ± 0.46 mg/100 g) and rutin (46.08 ± 0.63–109.08 ± 0.07 mg/100 g) were quantified in all four extracts. Caffeic acid (0.79 ± 0.18 mg/100 g) was only present in C. meyeri , whereas ferulic acid and apigenin were detected in three extracts in minor amounts. Our findings also pointed out to a marked variation in bioactivity and phytochemistry among the same plant species growing in different places. This is the first anticholinesterase and antioxidant study on most the Rosaceae species studied herein. Among them, Sorbus umbellata appears to be a promising herb due to its noticeable anti-AChE and antioxidant activities. [ABSTRACT FROM AUTHOR]

In the current study, the aqueous, dichloromethane, and methanol extracts of 12 samples of Viscum album L. collected on different host plants as well as two isolated compounds [syringin (VA-1) and 5,7-dimethoxyflavanone-4′- O -[5′′′- O - trans -cinnamoyl-β- d -apiofuranosyl]-β- d- glucopyranoside (VA-2)] were tested against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tryosinase (TYRO) enzymes at 2000 μg/mL by ELISA microtiter plate assays. Antioxidant activity of the extracts and compounds was evaluated by six in vitro methods [2,2-diphenyl-1-picrylhydrazyl (DPPH), N,N -dimethyl- p -phenylendiamine (DMPD), and nitric oxide radical scavenging assays, metal-chelation capacity, ferric-(FRAP), and phosphomolibdenum-reducing antioxidant power (PRAP)]. Total phenolic and flavonoid contents of the extracts were determined using Folin-Ciocaltaeu's and AlCl 3 reagents, respectively. None of the extracts had any marked inhibition against tyrosinase, while they exerted a low inhibition against AChE and BChE at 200 μg/mL. The aqueous and methanol extracts displayed a strong antioxidant activity in DPPH and DMPD radical quenching tests as well as FRAP and metal-chelation capacity assays. [ABSTRACT FROM AUTHOR]

The dichloromethane (DCM), ethyl acetate (EtOAc), and methanol extracts from the leaves, roots, and flowers of the five species of Gentiana ( Gentiana asclepiadea, Gentiana cruciata, Gentiana olivieri, Gentiana septemfida, and Gentiana verna) and Gentianella caucasea were investigated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and antioxidant effect using 2,2-diphenyl-1-picrylhydrazyl radical scavenging, metal-chelation capacity, and ferric-reducing antioxidant power assays. Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. The presence of some characteristic compounds found in Gentiana species (gentiopicroside, swertiamarin, isoorientin, isovitexin and vitexin) was analyzed in the extracts by thin layer chromatography. The flower DCM extract of G. verna exerted the highest inhibition against AChE (53.65 ± 1.03%), whereas the root EtOAc extract of G. cruciata was the most effective in BChE inhibition assay (50.72 ± 0.75%) at 100 μg ml− 1. The extracts of G. verna were also found to be more active in the antioxidant tests. [ABSTRACT FROM AUTHOR]

The ethyl acetate and ethanol extracts obtained from eight varieties (Faikbey, Y-1779, CI-8357, Cheokota, Seydişehir, Y-330, Sivas and YVD-18) of oat (Avena sativa L.), one variety (Larende) of barley (Hordeum vulgare L.), one variety (Tatlicak 97) of triticale (Triticale sp.) and one rye variety (Aslim 95) (Secale cereale L.) were investigated for their antioxidant effects in seven test systems. Anticholinesterase activity of the extracts was examined by enzyme-linked immunosorbent assay (ELISA) microplate reader. Total phenol and flavonoid contents were calculated using Folin Ciocalteau and AlCl3 reagents, respectively. All of the extracts were ineffective in cholinesterase inhibition assays and had weak-to-moderate activity in antioxidant assays. The extracts exerted better activity in iron-chelation capacity ranging between 43.17 ±  2.04 and 62.97 ± 1.29%. Triticale extracts showed higher activity in reducing power experiments. A notable difference in the results of the antioxidant activity assays was observed among the oat varieties. [ABSTRACT FROM AUTHOR]

Abstract: In the current work, the acetone, ethyl acetate, and ethanol extracts and essential oils of the twigs and needles of five Turkish Pinus species; P. brutia, P. halepensis, P. nigra, P. pinea, and P. sylvestris along with pycnogenol (the bark extract of P. pinaster) were examined for their inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at 200μgmL−1. Their antioxidant activity was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and N,N-dimethyl-p-phenylendiamine (DMPD) radical scavenging, metal-chelation, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were determined by Folin–Ciocalteau and AlCl3 reagents, respectively. GC–MS technique was applied for compositional profile of the essential oils of the tested species. Accordingly, the best AChE and BChE inhibition was caused by the twig essential oil (83.91±3.95%) and the needle ethanol extract (82.47±5.57%) of P. halepensis, respectively. Pycnogenol also caused a remarkable inhibition against AChE (63.33±0.22%) and BChE (83.67±0.22%). The extracts and essential oils usually showed a strong activity in the antioxidant assays. Pycnogenol exhibited a potent antioxidant effect and had the richest total phenol content. In the essential oils, α- and β-pinene were identified the major components. These results reveal that the Pinus species and pycnogenol are the potential sources of active metabolites with cholinesterase and antioxidant properties. [Copyright &y& Elsevier]