Hyperguanyes A and B, two new PPAPs from the branches and leaves of Hypericum perforatum L. with anti-cholinesterase activities.

Two new polycyclic polyprenylated acylphloroglucinols, hyperguanyes A and B (1-2) together with eight known compounds (3-10), were isolated from Hypericum perforatum L. Their structures were determined by using comprehensive spectroscopic techniques and quantum chemical calculation. The in vitro anti-cholinesterase activity of all compounds were studied. Among them, compounds 1-4, 8 and 9 exhibited anti-AchE and anti-BchE effects with IC50 ranging from 0.34 ± 0.04 to 15.68 ± 0.54 µM.

Linking traditional medicine to modern phytotherapy: Chemical characterization and assessment of antioxidant and anticholinesterase effects in vitro of a natural Persian remedy for dementia.

Several natural remedies are used in the Traditional Persian Medicine (TPM) to prevent dementia, but their efficacy is debated. In this work, an improved "Safoof-e-Nesyan" formulation described in the "Qarabadin-e-Azam" pharmacopoeia was developed, and its chemical composition and antioxidant and anti-cholinesterase properties were assessed. The formulation contains a mixture (FM) of Cinnamomum cassia (CC), C. verum (CV), Pistacia lentiscus (PL), Rheum palmatum (RP), Syzygium aromaticum (SA), and Zingiber officinalis (ZO) powdered plants. Its total phenolic content is 110.45 mg GAE/g, while the total flavonoid content is 6.28 mg RE/g. 66 secondary metabolites (mainly tannins, flavonoids, anthraquinones, and gingerols) were identified by UPLC-QToF-MS analysis. FM exerts antioxidant effects by scavenging radicals, and by reducing and chelating metals such as Mb, Cu and Fe. The anticholinesterase activity of one gram of the FM equals that of 3.60 mg of the reference drug galantamine, on both acetyl- and butyryl-cholinesterase. Correlations between specific compounds and bioactivities were highlighted by multivariate analysis of data: lyoniresinol 9'-glucoside strongly correlates with antiradical activities on DPPH and ABTS and reducing activity on Cu, and with anti-AChE effects. Most of the identified flavonoids and the ellagic acid derivatives positively correlate with the reducing activity on Fe and Mb, and with anti-BChE effects. Finally, a tablet formulation of the FM was developed, and its physical properties were preliminarily assessed. Overall, our results indicate that the FM may be a useful natural remedy for dementia, although further safety and efficacy assessments in vivo are required.

Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity.

Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 µM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 µM), but 90-fold more water-soluble.

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups.

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 µM and 28.37 ± 1.85 µM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 µM and 6.05 ± 1.17 µM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 µM). It is worth noting that 3-aminoquinoline derivatives 12a-12d exhibited better drug-like properties.

The Therapeutic Potential of Ethnomedicinally Important Anatolian Thyme Species: A Phytochemical and Biological Assessment.

Thyme has been used for various therapeutic purposes in many different cultures, which makes it one of the most riveting medicinal plants throughout history. From its beneficial effects on the respiratory tract or the gastrointestinal system, to its unique skin-related activities, the investigation of the medicinal properties of thyme has always been an alluring topic for researchers aiming to develop conventional medications from this traditional herb. With an incentive to contribute to the extensive thyme research, three Thymus L. species namely Thymus cariensis Hub-Mor. & Jalas (endemic), Thymus praceox subsp. grossheimii (Ronniger) Jalas, and Thymus pubescens Boiss. et Kotschy ex Celak from Turkey were deeply investigated within this study. The analysis of the phytochemical constituents of the extracts was conducted by LC-MS/MS. 12 biologically important secondary metabolites (p-coumaric acid, caffeic acid, salicylic acid, quinic acid, fumaric acid, vanillin, malic acid, rutin, apigenin, naringenin, and nicotiflorin) were detected in all extracts. Their total phenolic and flavonoid contents were calculated (11.15 ± 0.17-61.12 ± 2.59 µg PEs/mg extract, 2.53 ± 0.04-40.28 ± 0.92 µg QEs/mg extract, respectively), and the antioxidant potential of the extracts was evaluated by DPPH and ABTS radical scavenging and CUPRAC activity methods, accordingly, the extracts were shown to possess significant antioxidant activity. Among them, Thymus cariensis Hub-Mor. & Jalas was the most active with IC50 values of 34.97 ± 1.00 µg/ml and 9.98 ± 0.04 µg/ml regarding the DPPH and ABTS radical scavenging assays, respectively, and an A0.5 value of 5.80 ± 0.02 µg/ml according to CUPRAC activity method. Their anticholinesterase, antityrosinase, and antiurease activities were also tested, Thymus cariensis Hub-Mor. & Jalas (35.61 ± 1.20%) and Thymus pubescens Boiss. et Kotschy ex Celak aerial part extract (33.49 ± 1.39%) exhibited moderate antibutyrylcholinesterase activity at 200 µg/ml concentration. The results of the cell viability assay indicated that the extracts demonstrated moderate-to-low cytotoxicity on A498 human renal cell lines. Furthermore, all studied extracts exerted noteworthy antimicrobial activity, especially against Candida tropicalis (MIC values: 19.53-78.12 µg/ml). The presented data substantiates the use of thyme extracts as therapeutic agents in both ethnomedicine and conventional therapies.

Polyphenols composition and the biological effects of six selected small dark fruits.

The health-promoting activities of fruits are in the limelight in view of the growing risks posed by civilisational diseases and are connected with polyphenols. The present study examined bilberry, blueberry, blackcurrant, redcurrant, cherry and plum for their polyphenolic content and biological activities. The contents of total polyphenolic compounds and their subclasses were determined. Liquid chromatography high-resolution mass spectrometry was used to characterise the polyphenolic profiles. Small dark fruits' antioxidant, anti-inflammatory, and anti-cholinesterase activities were also extensively determined. Significant qualitative and quantitative differences in the analysed fruits' polyphenols composition and biological activities were demonstrated. The highest polyphenolic contents and antioxidant activities were established in blackcurrant fruit, but bilberry also had our attention due to an additional mild influence on antioxidant enzymes. The condensed tannin content in small dark fruits is developed. All tested fruits exhibit anti-inflammatory and anti-cholinesterase activities.

Chemical Composition, Acetylcholine Esterase and Anti-bacterial Activities of Essential Oils of Elaeosilenum thapsioides (Desf.) Maire from Algeria.

BACKGROUND: Traditionally, the Algerian medicinal plant Elaeosilenum thapsioides (Desf.) Maire has been used for many diseases. The present research work aims to explore the chemical and biological characterization of its essential oil. METHODS: The essential oils were obtained by hydrodistillation of different Elaeosilenum thapsioides (Apiaceae) aerial parts samples collected from two different regions (Mahouane and Megres) from Setif, Eastern Algeria. The chemical characterization of the obtained essential oils is reported here for the first time. Besides, they were evaluated for their in vitro Acetylcholinesterase (AChE) inhibitory activity involved in Alzheimer's disease using Ellman's spectrophotometric method. RESULTS: Additionally, their in vitro antimicrobial activity was assessed by the disc diffusion method. Both activities were performed at various oil concentrations. The GC/MS analysis of the essential oils from aerial parts (leaves, stems, flowers, and seeds) of E. thapsioides identified 47 constituents. Monoterpene hydrocarbons were the main components, ranging from 72.78 to 99.13%. Oxygenated monoterpenes and oxygenated sesquiterpenes ranged between 1.37 and 17.25% and 0.12 and 3.53% in essential oils from leaves and stems. Sesquiterpene hydrocarbons were present in small to large quantities in the essential oils of both populations, ranging from 0.69 to 13.44%. The presence of m-Methoxybenzyl isothiocyanate was recorded in stems essential oils from Mahouane and leaves essential oils from Merges, which was 9.73% and 3.72%, respectively. CONCLUSION: The stems essential oils obtained from plants collected in Mahouane showed the highest AChE inhibitory activity. The highest anti-bacterial activity was shown by the essential oil obtained from Megres leaves against Bacillus cereus ATCC 11778. The oils exhibited a moderate inhibitory activity in both tests.

Morindaquinone, a new bianthraquinone from Morinda coreia roots.

Phytochemical investigation of the roots of Morinda coreia led to the isolation of one new bianthraquinone, morindaquinone (1), together with 12 known compounds, soranjidiol (2), rubiadin-1-methyl ether (3), 2-methoxy-1,3,6-trihydroxyanthraquinone (4), 1-hydroxy-2-methylanthraquinone (5), tectoquinone (6), nordamnacanthal (7), damnacanthal (8), 2-formylanthraquinone (9), 3-hydroxy-2-hydroxymethylanthraquinone (10), lucidin-ω-methyl ether (11), scopoletin (12) and (+)-mellein (13). The structures of these compounds were determined on the basis of extensive spectroscopic analyses, as well as by comparison with literature reports. Compound 1 was the first example of bianthraquinone found in the genus Morinda, whereas compound 13 was firstly isolated from this genus. Among them, compounds 2, 7, 8 and 10 exhibited moderate to weak cytotoxicity against human cervical (HeLa), human colon (HT 29) and human breast (MCF-7) cell lines, while compounds 6 and 9 - 11 showed weak anti-acetylcholinesterase activity.

Synthesis, biological evaluation and modeling of hybrids from tetrahydro-1H-pyrazolo[3,4-b]quinolines as dual cholinestrase and COX-2 inhibitors.

New tetrahydro-1H-pyrazolo[3,4-b]quinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against hAChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1H-pyrazolo[3,4-b]quinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease.

Bioactive Compounds, Antioxidant Activity and Inhibition of Key Enzymes Relevant to Alzheimer's Disease from Sweet Pepper (Capsicum annuum) Extracts.

Sweet pepper is a non-pungent chili of the Capsicum annuum species and is an important ingredient in daily diets due to its characteristics such as pungency, aromas, and flavors. Sweet pepper is a rich source of bioactive compounds such as phenols, carotenoids, and flavonoids, which can promote potential health benefits against various non-communicable diseases. However, research focused on anti-Alzheimer's disease (AD) properties of sweet peppers is limited. Thus, this study aimed investigate bioactive compounds (flavonoids, phenolic acids, and carotenoids), antioxidant activity and anti-AD properties of four colored sweet peppers (green, red, orange, and yellow) via their abilities to inhibit key enzymes relevant to AD [acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-secretase (BACE1)]. Extraction solvents [hexane, ethyl acetate, and 70% (v/v) aqueous ethanol] were also investigated. Results suggested that yellow sweet pepper have the highest content of flavonoids, while green sweet pepper have the highest contents of phenolic acids and red sweet peppers have the highest content of carotenoids. In terms of anti-AD properties, green sweet peppers exhibited the highest antioxidant, anti-BChE, and anti-BACE1 activities; however, yellow sweet pepper extract exhibited the highest amounts of AChE inhibition. Bioactive compounds in sweet red peppers may therefore have anti-AD properties, and may be useful for AD prevention.

New 4-N-phenylaminoquinoline derivatives as antioxidant, metal chelating and cholinesterase inhibitors for Alzheimer's disease.

A series of new 4-N-phenylaminoquinoline derivatives were designed, synthesized, and their anticholinesterase activities, 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, metal-chelating ability were tested. Among them, compounds 11j, 11k and 11l had comparable inhibition activities to reference drug galantamine both in AChE and in BChE. Especially, compound 11j revealed the most potent inhibition to eeAChE and eqBChE with IC50 values of 1.20 µM and 18.52 µM, respectively. Furthermore, both kinetic analysis of AChE inhibition and molecular docking study indicated that compound 11j was mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE, and propidium iodide displacement assay showed significant displacement of propidium iodide with compound 11k (25.80%) from PAS of eeAChE. More importantly, compound 11l displayed excellent DPPH radical scavenging activity (84% at 1 mg/mL), and its EC50 value was 0.328 µM. In addition, compounds 11a, 11j, 11k and 11l exhibited obvious biometal chelating abilities toward Al3+, Fe2+, Cu2+ and Zn2+ ions. Taken together, 4-N-phenylaminoquinoline derivatives targeting multiple pathogenetic factors deserve further investigation for treatment of AD.

Chlorinated tacrine analogs: Design, synthesis and biological evaluation of their anti-cholinesterase activity as potential treatment for Alzheimer's disease.

In search of potent acetyl cholinesterase inhibitors with low hepatotoxicity for the treatment of Alzheimer's disease, introduction of a chloro substitution to tacrine and some of its analogs has proven to be beneficial in maintaining or potentiating the cholinesterase inhibitory activity. Furthermore, it was found to be able to reduce the hepatotoxicity of the synthesized compounds, which is the main target of the study. Accordingly, a series of new 4-(chlorophenyl)tetrahydroquinoline derivatives, was synthesized and characterized. The synthesized compounds were evaluated for their in vitro and in vivo anti-cholinesterase activity using tacrine as a reference standard. Furthermore, they were investigated for their hepatotoxicity compared to tacrine. The obtained biological results revealed that all synthesized compounds displayed equivalent or significantly higher anti-cholinesterase activity and lower hepatotoxicity in comparison to tacrine. In addition, in silico drug-likeness of the synthesized compounds were predicted and their practical logP were assessed indicating that all synthesized compounds can be considered as promising hits/leads. Furthermore, docking study of the compound showing the highest in vitro anticholinesterase activity was performed and its binding mode was compared to that of tacrine.

Essential oil of Citrus lumia Risso: Phytochemical profile, antioxidant properties and activity on the central nervous system.

The use of essential oils (EOs) is known since long time in traditional medicine and aromatherapy for the management of various oxidative stress-related disorders and has been further increased recently for their neuroprotective and anti-aging potentials as well as for reducing anxiety and stress. The purpose of this work was to evaluate, for the first time, the chemical composition of Citrus lumia Risso EO and its antioxidant, anti-cholinesterase, and neuroactive properties by cell-free and cell-based assays. The EO has shown strong antioxidant and free radical scavenging properties, particularly in hydrogen atom transfer based assays (ß-carotene bleaching and ORAC, IC50 22 µg/mL and 46 µg/mL, respectively), that can be attributed to the high content of monoterpenes, especially d-Limonene (48.905%), and Linalool (18.245%). Furthermore, the EO has shown an interesting anti-acetylcholinesterase activity (IC50 258.25 µg/mL). Data from MTT analysis indicate that the cytotoxicity of EO, evaluated on L929 mouse fibroblasts, is very low, with an IC50 higher than 500 µg/mL at 48 h. Rat neuronal networks subjected to EO showed a concentration-dependent inhibition of spontaneous electrical activity. Results indicate that C. lumia EO could be an important source of natural antioxidants suggesting an important preventive role in the onset of oxidative stress-related pathologies.

Effect of pomegranate extracts on brain antioxidant markers and cholinesterase activity in high fat-high fructose diet induced obesity in rat model.

BACKGROUND: To investigate beneficial effects of Pomegranate seeds oil (PSO), leaves (PL), juice (PJ) and (PP) on brain cholinesterase activity, brain oxidative stress and lipid profile in high-fat-high fructose diet (HFD) induced-obese rat. METHODS: In vitro and in vivo cholinesterase activity, brain oxidative status, body and brain weight and plasma lipid profile were measured in control rats, HFD-fed rats and HFD-fed rats treated by PSO, PL, PJ and PP. RESULTS: In vitro study showed that PSO, PL, PP, PJ inhibited cholinesterase activity in dose dependant manner. PL extract displayed the highest inhibitory activity by IC50 of 151.85 mg/ml. For in vivo study, HFD regime induced a significant increase of cholinesterase activity in brain by 17.4% as compared to normal rats. However, the administration of PSO, PL, PJ and PP to HDF-rats decreased cholinesterase activity in brain respectively by 15.48%, 6.4%, 20% and 18.7% as compared to untreated HFD-rats. Moreover, HFD regime caused significant increase in brain stress, brain and body weight, and lipid profile disorders in blood. Furthermore, PSO, PL, PJ and PP modulated lipid profile in blood and prevented accumulation of lipid in brain and body evidenced by the decrease of their weights as compared to untreated HFD-rats. In addition administration of these extract protected brain from stress oxidant, evidenced by the decrease of malondialdehyde (MDA) and Protein carbonylation (PC) levels and the increase in superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. CONCLUSION: These findings highlight the neuroprotective effects of pomegranate extracts and one of mechanisms is the inhibition of cholinesterase and the stimulation of antioxidant capacity.

Evaluation of Antioxidant, Antidiabetic and Anticholinesterase Activities of Smallanthus sonchifolius Landraces and Correlation with Their Phytochemical Profiles.

The present study aimed to investigate the phytochemical profile of leaf methanol extracts of fourteen Smallanthus sonchifolius (yacon) landraces and their antioxidant, anticholinesterase and antidiabetic activities that could lead to the finding of more effective agents for the treatment and management of Alzheimer's disease and diabetes. For this purpose, antioxidant activity was assessed using different tests: ferric reducing ability power (FRAP), 2,2-diphenyl-1-picryl hydrazyl (DPPH), nitric oxide (˙NO) and superoxide (O2˙-) scavenging and lipid peroxidation inhibition assays. Anticholinesterase activity was investigated by quantifying the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, whereas antidiabetic activity was investigated by α-amylase and α-glucosidase inhibition tests. To understand the contribution of metabolites, phytochemical screening was also performed by high performance liquid chromatography-diode array detector (HPLC-DAD) system. Among all, methanol extract of PER09, PER04 and ECU44 landraces exhibited the highest relative antioxidant capacity index (RACI). ECU44 was found to be rich in 4,5-di-O-caffeoylquinic acid (CQA) and 3,5-di-O-CQA and displayed a good α-amylase and α-glucosidase inhibition, showing the lowest IC50 values. Flavonoids, instead, seem to be involved in the AChE and BChE inhibition. The results of this study revealed that the bioactive compound content differences could be determinant for the medicinal properties of this plant especially for antioxidant and antidiabetic activities.

Progress in Studies on Rutaecarpine. II.--Synthesis and Structure-Biological Activity Relationships.

Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on rutaecarpine have included isolation from new natural sources, development of new synthetic methods for its total synthesis, the discovery of new biological activities, metabolism, toxicology, and establishment of analytical methods for determining rutaecarpine content. The present review focuses on the synthesis, biological activities, and structure-activity relationships of rutaecarpine derivatives, with respect to their antiplatelet, vasodilatory, cytotoxic, and anticholinesterase activities.

Methyl jasmonate enhances memory performance through inhibition of oxidative stress and acetylcholinesterase activity in mice.

AIMS: Current research effort focuses on the development of safer natural compounds with multipronged mechanisms of action that could be used to ameliorate memory deficits in patients with Alzheimer's disease, as cure for the disease still remains elusive. In this study, we evaluated the effect of methyl jasmonate (MJ), a naturally occurring bioactive compound on memory, acetylcholinesterase activity and biomarkers of oxidative stress in mice. MAIN METHODS: Male Swiss mice were treated with intraperitoneal injection of MJ (10-40 mg/kg) alone or in combination with scopolamine (3mg/kg) once daily for 7 days. Thirty minutes after the last treatment, memory functions were assessed using Y-maze and object recognition tests. Thereafter, acetylcholinesterase activity and levels of biomarkers of oxidative stress were assessed in mice brains using standard biochemical procedures. KEY FINDINGS: MJ significantly enhanced memory performance and reversed scopolamine-induced cognitive impairment in mice. MJ demonstrated significant inhibition of acetylcholinesterase activity suggesting increased cholinergic neurotransmission. It further decreased malondialdehyde concentrations in mouse brain indicating antioxidant activity. Moreover, MJ significantly increased glutathione levels and activity of antioxidant enzymes (catalase and superoxide dismutase) in mice brains. The increased oxidative stress; evidenced by elevated levels of malondialdehyde and decreased antioxidant defense systems in scopolamine-treated mice was attenuated by MJ. SIGNIFICANCE: The results of this study suggest that MJ may be useful in conditions associated with memory dysfunctions or age-related cognitive decline. The positive effect of MJ on memory may be related to inhibition of oxidative stress and enhancement of cholinergic neurotransmission through inhibition of acetylcholinesterase activity.