Phytochemical Profiling and Biological Activities of Pericarps and Seeds Reveal the Controversy on "Enucleation" or "Nucleus-Retaining" of Cornus officinalis Fruits.

The fruits of Cornus officinalis are used not only as a popular health food to tonify the liver and kidney, but also as staple materials to treat dementia and other age-related diseases. The pharmacological function of C. officinalis fruits with or without seeds is controversial for treating some symptoms in a few herbal prescriptions. However, the related metabolite and pharmacological information between its pericarps and seeds are largely deficient. Here, comparative metabolomics analysis between C. officinalis pericarps and seeds were conducted using an ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, and therapeutic effects were also evaluated using several in vitro bioactivity arrays (antioxidant activity, α-glucosidase and cholinesterase inhibitory activities, and cell inhibitory properties). A total of 499 secondary metabolites were identified. Thereinto, 77 metabolites were determined as key differential metabolites between C. officinalis pericarps and seeds, and the flavonoid biosynthesis pathway was identified as the most significantly different pathway. Further, 47 metabolites were determined as potential bioactive constituents. In summary, C. officinalis seeds, which demonstrated higher contents in total phenolics, stronger in vitro antioxidant activities, better α-glucosidase and butyrylcholinesterase inhibitory activities, and stronger anticancer activities, exhibited considerable potential for food and health fields. This work provided insight into the metabolites and bioactivities of C. officinalis pericarps and seeds, contributing to their precise development and utilization.

New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation.

In this study, two series of compounds were designed and synthesized, bearing thiourea and benzamide derivatives at position 2 of 4-subtituted-2-aminothiazole, respectively. Then, the inhibition potency of all final compounds for cholinesterase enzymes were evaluated. Among the thiourea derivatives, 3c (IC50 = 0.33 µM) was identified as the most potent and selective butyrylcholinesterase inhibitor. Additionally, benzamide derivative 10e (AChE IC50 = 1.47 and BChE IC50 = 11.40 µM) was found as a dual cholinesterase inhibitor. The type of inhibition for both compounds was determined by kinetic studies and the results showed that the compounds were mixed type inhibitors. Moreover, all title compounds were investigated in terms of their antioxidant (DPHH, ORAC) and metal chelator activities. In addition, the neuroprotective effects of selected compounds (3c, 3e, 6c, 6e and 10e) against H2O2-induced damage in the PC12 cell line were tested. The experimental findings demonstrated that thiourea-derived 6e (40.4 %) and benzamide-derived 10e (37.8 %) have a neuroprotective effect of about half as ferulic acid at 10 µM. Subsequently, the cytotoxicity of selected compounds was examined by the MTT assay, and the compounds were found not to have cytotoxic effect on the PC12 cell line in 24 h. Additionally, compounds 6e and 10e were also found to be more effective in inhibiting the release of IL-1ß, IL-6, TNF-α and NO compared to other selected compounds in this study.

Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents.

In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 µM, butyrylcholinesterase [BChE] IC50 = 14.7 µM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 µM, BChE IC50 = 0.9 µM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual cholinesterase inhibitors. Then, selected compounds were investigated in terms of their metal chelation activity. Moreover, their neuroprotective effects against H2 O2 -induced damage in the PC12 cell line were evaluated at 10 µM and the results showed that the neuroprotective effect of 3e was 53% compared with the reference ferulic acid (77%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing lipopolysaccharides-induced interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production in the human monocyte derived from patient with acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.

Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer's disease.

In this work, we designed, synthesised and biologically investigated a novel series of 14 N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer's disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6-13 and 16-21 that were characterised by 1H, 13 C, 31 P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman's method. The most inhibitory activity against AChE exhibited compound 8 with an IC50 value of 6.11 nM and against BChE 13 with an IC50 value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay.

Resveratrol-Maltol and Resveratrol-Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure.

New resveratrol-thiophene and resveratrol-maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol-thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe3+ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6-12.6, suggesting that Fe3+ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol-maltol hybrids were recorded, giving additional information on the molecules' intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases.

Bioactivity-Guided Separation of Anti-Cholinesterase Alkaloids from Uncaria rhynchophlly (Miq.) Miq. Ex Havil Based on HSCCC Coupled with Molecular Docking.

As an important source of cholinesterase inhibitors, alkaloids in natural products have high potential value in terms of exerting pharmacological activities. In this study, a strategy for targeted preparation of cholinesterase inhibitors in Uncaria rhynchophlly (Miq.) Miq. ex Havil (UR) by high-speed counter-current chromatography was provided. In the method, a two-phase polar solvent system composed of ethyl acetate/n-butanol/water (1:4:5, v/v/v) was used, which isolated five alkaloids from the UR extract for the first time. All alkaloids were identified by HR-ESI-MS and NMR as 7-epi-javaniside (1), vincosamide (2), strictosamide (3), cadambine (4), and 3α-dihydrocadambine (5). The poorly resolved compounds 2 and 3 were separated by preparative HPLC (prep-HPLC). Among them, compounds 1, 4, and 5 were firstly obtained from UR. The purity of these plant isolates was 98.8%, 98.7%, 99.2%, 95.7%, and 98.5%, respectively. Compounds 1-5 exhibited an inhibitory effect on acetyl-cholinesterase and butyryl-cholinesterase with an IC50 from 1.47 to 23.24 µg/mL and 1.01 to 18.24 µg/mL. Molecular docking and inhibitory activities indicated that compound 1 showed stronger inhibitory activity on acetyl-cholinesterase and butyryl-cholinesterase.

Antioxidant, anticholinesterase and antibacterial activities of Stachys guyoniana and Mentha aquatica.

CONTEXT: Stachys guyoniana Noë ex. Batt. and Mentha aquatica L. are two Algerian Lamiaceae used in folk medicine. OBJECTIVE: To investigate their antioxidant, anticholinesterase and antibacterial activities. MATERIAL AND METHODS: n-Butanol (BESG), ethyl acetate (EESG) and chloroform (CESG) extracts of S. guyoniana and methanol (MEMA) and chloroform (CEMA) aerial part extracts of M. aquatica and methanol (MERMA) and acetone (AERMA) roots extracts of M. aquatica were evaluated for their antioxidant activity by the ß-carotene-linoleic acid, DPPH• and ABTS•+ scavenging, CUPRAC and metal chelating assays. The anticholinesterase activity was tested against AChE and BChE. The antibacterial activity was assessed by MICs determination against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella heidelberg, Klebsiella pneumoniae, Enterobacter aerogenes and Morganella morganii strains. RESULTS: In the ß-carotene test, the CESG (IC50: 2.3 ± 1.27 µg/mL) exhibited the highest activity. The BESG was the best scavenger of DPPH• (IC50: 2.91 ± 0.14 µg/mL). In the ABTS test, AERMA was the most active (IC50: 4.21 ± 0.28 µg/mL). However, with the CUPRAC, the BESG exhibited the best activity (A0.50: 0.15 ± 0.05 µg/mL) and was active in metal chelating assay with 48% inhibition at 100 µg/mL. The BESG was the best AChE inhibitor (IC50: 5.78 ± 0.01 µg/mL) however, the AERMA showed the highest BChE inhibitory activity (IC50: 19.23 ± 1.42 µg/mL). The tested extracts exhibited a good antibacterial activity. CONCLUSION: This study demonstrated good antioxidant, anticholinesterase and antibacterial potential of S. guyoniana and M. aquatica, which fits in well with their use in folk medicine.

Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease.

Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 ± 0.04 µM) and butyrylcholinesterase (BuChE, IC50 = 6.11 ± 0.15 µM). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced Aß aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aß. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1ß, TNF-α; IC50 = 0.62 ± 0.07 µM, 1.78 ± 0.21 µM, 1.31 ± 0.28 µM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood-brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD.

Phytochemical Screening, In vitro Antioxidant and Enzyme Inhibitory Properties, and Acute Toxicity of Extracts from the Aerial Parts of Ephedra nebrodensis, a Source of Bioactive Compounds.

BACKGROUND: Due to the strong association between the chemistry of medicinal plants and their biological properties, it is important to determine their phytochemical composition to justify experimental tests. OBJECTIVE: The aim of this study was to evaluate the in vitro antioxidant and the enzyme inhibitory properties and to identify the bioactive compounds present in the extracts of Ephedra nebrodensis growing in Algeria. METHODS: Total phenolic and flavonoids content in these extracts were quantified by Folin- Ciocalteu and aluminum chloride methods. The antioxidant capacity was assessed using DPPH, ABTS, ß-carotene/linoleic acid, CUPRAC and FRAP assays, and in vitro cholinesterase activity against acetylcholinesterase and butyrylcholinesterase were evaluated. The chemical constituents of the extracts were analyzed by high-performance liquid chromatography coupled with mass spectrometric detection and gas chromatography. For the acute toxicity study, extracts were administered to mice at single dose of 2 g/kg and 5 g/kg by gavage. RESULTS: Plant extracts were rich in phenolic compounds. Ethyl acetate extract presented the highest phenolic (238.44 ± 1.50 µg GAE /mg of extract) and flavonoid (21.12 ± 0.00 µg QE /mg of extract) contents. Likewise, ethyl acetate extract showed potent radical scavenging and reducing properties. Ethanol-acetone extract showed inhibitory activity against acetylcholinesterase, and was a potent inhibitor of butyrylcholinesterase. In all extracts, flavonoids were the most abundant compounds. The phytochemical investigation showed the presence of alkaloids (ephedrine and pseudo-ephedrine). In the acute toxicity, the LD50 was superior to 5 g/kg body weight. There were no alterations in the histology of the liver and kidneys. CONCLUSION: This study demonstrated a good antioxidant potential and anticholinesterase activity of aerial parts of E. nebrodensis.

(-)-Grandiflorimine, a new dibenzopyrrocoline alkaloid with cholinesterase inhibitory activity from Illigera grandiflora.

A new dibenzopyrrocoline alkaloid, (-)-grandifloramine (1), together with five known ones, actinodaphnine (2), N-methyllaurotetanine (3), boldine (4), lindcarpine (5), and (+)-norboldine (6), were isolated from Illigera grandiflora W. W. Sm. et J. F. Jeff. The structure of 1 was identified by HRESIMS, 1D/2D NMR, and electronic circular dichroism (ECD) spectra. Compound 1 and 2 exhibited the moderate inhibitory activity against acetylcholinesterase and 3 showed moderate butyrylcholinesterase inhibitory activity. This is the first report of the chemical constituents of I. grandiflora.

Design, synthesis and biological evaluation of new benzoxazolone/benzothiazolone derivatives as multi-target agents against Alzheimer's disease.

In this study, four series of compounds with benzoxazolone and benzothiazolone cores were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). Additionally, in order to shed light on the effect of the carbonyl groups of benzoxazolone/benzothiazolone, benzoxazole/benzothiazole-containing analogues were also synthesized and evaluated. Inhibition potency of all final compounds towards cholinesterase enzymes and their antioxidant activity were tested. Subsequently, the anti-inflammatory activity, cytotoxicity, apoptosis, and Aß aggregation inhibition tests were also performed for selected compounds. The results indicated that compounds 11c, a pentanamide derivative with benzothiazolone core, and 14b, a keton derivative with benzothiazolone core, were considered as promising multi-functional agents for further investigation against AD. The reversibility, kinetic and molecular docking studies were also performed for the compounds with the highest AChE 14b (eeAChE IC50 = 0.34 µM, huAChE IC50 = 0.46 µM) and BChE 11c (eqBChE IC50 = 2.98 µM, huBChE IC50 = 2.56 µM) inhibitory activities.

Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids.

Two series of dimethoxyindanone imbedded novel fluorinated spiropyrrolidine heterocyclic hybrids were synthesized employing two different less explored azomethine ylides and were measured for their efficiency as inhibitors for Alzheimer's disease. Among the spiropyrrolidine heterocyclic hybrids, the indole based fluorinated compound with a methoxy substituent at the meta- position of the aryl ring exhibited the utmost potent AChE and BChE inhibitory activities with an IC50 of 1.97 ± 0.19 µM and 7.08 ± 0.20 µM respectively. The plausible mechanism of inhibition on ChE receptors was unveiled via molecular docking studies.

Chemical composition and biological activities of an essential oil from the aerial parts of Artemisia Gmelinii weber ex Stechm.

The aerial parts of Artemisia gmelinii Weber ex Stechm were collected from the northeast of China. The essential oil was obtained by hydrodistillation and analysed by GC-MS. A set of 66 compounds were identified representing 99.1% of the oil composition. The major compounds in the oil were cyclobutaneethanol, endo-borneol, germacrene D, eucalyptol, selin-6-en-4α-ol, bisabolone oxide A, caryophyllene and terpinen-4-ol. Moreover, the essential oil was evaluated for its antioxidant, antidiabetic, and anticholinesterase activities in vitro. Additionally, the antioxidant potential of the oil was evaluated using DPPH and ABTS assays. The oil showed good antidiabetic activity with an IC50 of 63.2 µg/mL, which was similar to that of the positive control acarbose, and weak anticholinesterase activities. These findings demonstrated that the essential oil of Artemisia gmelinii may be a good natural antidiabetic.

Chemical composition, antioxidant, antibacterial and cholinesterase inhibitory activities of three Juniperus species.

The chemical composition, antioxidant, antibacterial and cholinesterase inhibitory activities of three Juniperus species were studied. The contents of total phenolic and 10 phenolic compounds were highest in Juniperus rigida Sieb.et Zucc., of which catechin and cumaric acid were the predominant phenolic compounds, but were lowest in Juniperus sibirica Burgsd. GC-MS analysis showed the highest contents of essential oils were in J. rigida (92.61%), followed by Juniperus formosana Hayata (87.30%) and J. sibirica (84.89%). The a-pinene was the most dominant compound in J. rigida (23.99%) and J. formosana (9.71%), however, it has not been detected in J. sibirica. Ethanol extracts showed the higher radical scavenging capacity in ABTS, FRAP and DPPH assays than essential oils. The essential oils and ethanol extracts of J.sibirica showed the strong antibacterial activity against Salmonella typhimurium and Escherichia coli. Three Juniperus species showed certain acetylcholinesterase and butyrylcholinesterase inhibitions and J. formosana showed better cholinesterase inhibitory.

The Essential Oil of Salvia rosmarinus Spenn. from Italy as a Source of Health-Promoting Compounds: Chemical Profile and Antioxidant and Cholinesterase Inhibitory Activity.

The chemical composition of the essential oil from Salvia rosmarinus Spenn. collected in Calabrian Ionian (R1) and Tyrrhenian (R2) coast (Southern Italy) was examined by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Essential oils are mainly characterized by monoterpene hydrocarbons (39.32-40.70%) and oxygenated monoterpenes (36.08-39.47%). The 1,8-cineole, α-pinene, camphor, and trans-caryophyllene are the most representative compounds. S. rosmarinus essential oils were investigated for their antioxidant activity by using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing ability power (FRAP), and ß-carotene bleaching tests. Additionally, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity assays were used to screen the neuroprotective effects of S. rosmarinus. R2 showed the highest antioxidant potential as confirmed by relative antioxidant capacity index (RACI) and exhibited a selective activity against AChE (half maximal inhibitory concentration, IC50, value of 41.86 µg/mL). These results suggest S. rosmarinus essential oil as a potential source of bioactive compounds.

Cholinesterase inhibitory isoquinoline alkaloids from Corydalis mucronifera.

Eight previously undescribed isoquinoline alkaloids, mucroniferanines H-M, together with 16 known isoquinoline alkaloids, were isolated from Corydalis mucronifera Maxim.. The structures of the previously undescribed compounds were elucidated by interpretation of 1D and 2D NMR spectroscopic and HRMS data, and their absolute configurations were established by computational electronic circular dichroism (ECD) calculations and X-ray diffraction data. Mucroniferanine L is reported as the first natural amide bond linked isoquinoline alkaloid dimer. The isolated compounds were evaluated for AChE and BuChE inhibitory activities and mucroniferanine H showed significant activities with IC50 values of 2.31 µM and 36.71 µM, respectively.

Monoterpene esters and aporphine alkaloids from Illigera aromatica with inhibitory effects against cholinesterase and NO production in LPS-stimulated RAW264.7 macrophages.

Three new monoterpene phenylpropionic acid esters, illigerates A-C (1-3), and one new aporphine alkaloid, illigeranine (4), as well as four known ones, actinodaphnine (5), nordicentrine (6), 8-hydroxy carvacrol (7), and 3-hydroxy-α,4-dimethyl styrene (8), were isolated from the tubers of Illigera aromatica. The structures of 1-4 were identified by HRESIMS, 1D and 2D NMR, and electronic circular dichroism spectra. Compound 1 potently inhibited NO production in LPS-stimulated RAW264.7 cells with an IC50 value of 18.71 ± 0.85 µM; compound 1, 3, and 4 showed moderate butyrylcholinesterase inhibitory activities with the IC50 values of 46.86 ± 0.65, 53.51 ± 0.71, and 31.62 ± 1.15 µM, respectively. Compound 4 showed weak AChE inhibitory activity with an IC50 value of 81.69 ± 2.07 µM, and compounds 5 and 6 possessed moderate AChE inhibitory activities with the IC50 values of 47.74 ± 1.66 and 40.28 ± 2.73 µM, respectively. This paper provides a chemical structure and bioactive foundation for using I. aromatica as an herbal medicine.

Effect of bioclimatic area on the composition and bioactivity of Tunisian Rosmarinus officinalis essential oils.

The chemical composition of eight Tunisian Rosmarinus officinalis L. populations (A-H) from different bioclimatic areas has been examined by gas chromatography (GC) and GC-mass spectrometry. The essential oils are characterised by high amounts of oxygenated monoterpenes (58.2-71.7%) followed by monoterpene hydrocabons (15.1-26.7%). 1,8-Cineole, camphor, α-pinene and borneol are the main representative components. The antioxidant activity was investigated by 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), ferric reducing ability power assay and ß-carotene bleaching test. Samples showed antiradical activity by inhibiting DPPH radical with IC50 values ranging from 375.3 to 592.8 µg mL(- 1) for samples F and A, respectively. Sample A also showed the most promising activity in ß-carotene bleaching test (IC50 of 31.9 µg mL(- 1)). The essential oils were also screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Sample G showed the highest activity against AChE (IC50 of 64.7 µg mL(- 1)) while sample D (IC50 of 29.5 µg mL(- 1)) exhibited the most potent activity against BChE.

Chemistry and functional properties in prevention of neurodegenerative disorders of five Cistus species essential oils.

The chemical composition of Cistus creticus, Cistus salvifolius, Cistus libanotis, Cistus monspeliensis and Cistus villosus essential oils has been examined by GC and GC-MS analysis. Height-nine constituents were identified in C. salvifolius oil, sixty in C. creticus, fifty-six in C. libanotis, fifty-four in C. villosus, forty-five in C. monspeliensis. Although the five species belong to the same genus, the composition showed interesting differences. Essential oils were screened also for their potential antioxidant effects (by DPPH, ABTS, FRAP and ß-carotene bleaching test) and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, useful for prevention and treatment of Alzheimer's disease. C. monspeliensis exhibited the most promising activity in ß-carotene bleaching test (IC50 of 54.7 µg/mL). In FRAP test C. libanotis showed a value of 19.2 µM Fe(II)/g. C. salvifolius showed the highest activity against AChE (IC50 of 58.1 µg/mL) while C. libanotis, C. creticus, C. salvifolius demonstrated a good inhibitory activity against BChE with IC50 values of 23.7, 29.1 and 34.2 µg/mL, respectively. Overall our results could promote the use of the essential oil of different Cistus species as food additives and for formulation of herbal infusion or nutraceutical products.