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Alzheimer's disease (AD) is a main cause of dementia, accounting for up to 75% of all dementia cases. Pathophysiological processes described for AD progression involve neurons and synapses degeneration, mainly characterized by cholinergic impairment. This feature makes acetylcholinesterase inhibitors (AChEi) the main class of drugs currently used for the treatment of AD dementia phase, among which galantamine is the only naturally occurring substance. However, several plant species producing diverse classes of alkaloids, coumarins, terpenes, and polyphenols have been assessed for their anti-AChE activity, becoming potential candidates for new anti-AD drugs. Therefore, this mini-review aimed to recapitulate last decade studies on the anti-AChE activity of plant species, their respective extracts, as well as isolated compounds. The anti-AChE activity of extracts prepared from 54 plant species pertaining 29 families, as well as 36 isolated compounds were classified and discussed according to their anti-AChE pharmacological potency to highlight the most prominent ones. Besides, relevant limitations, such as proper antioxidant assessment, and scarcity of toxicological and clinical studies were also discussed in order to help researchers out with the bioprospection of potentially new AChEi.

Alzheimer’s disease (AD) is one of the most common forms of dementia and is associated with a decline in cognitive function and language ability. The deficiency of the cholinergic neurotransmitter known as acetylcholine (ACh) is associated with AD. Acetylcholinesterase (AChE) hydrolyses ACh and inhibits the cholinergic transmission. Furthermore, both AChE and butyrylcholinesterase (BChE) plays important roles in early and late stages of AD. Therefore, the inhibition of either or both cholinesterase enzymes represent a promising therapeutic route for treating AD. In this study, a large-scale classification structure–activity relationship model was developed to predict cholinesterase inhibitory activities as well as revealing important substructures governing their activities. Herein, a non-redundant dataset constituting 985 and 1056 compounds for AChE and BChE, respectively, was obtained from the ChEMBL database. These inhibitors were described by 12 sets of molecular fingerprints and predictive models were developed using the random forest algorithm. Evaluation of the model performance by means of Matthews correlation coefficient and consideration of the model’s interpretability indicated that the SubstructureCount fingerprint was the most robust with five-fold cross-validated MCC of [0.76, 0.82] for AChE and BChE, respectively, and test MCC of [0.73, 0.97]. Feature interpretation revealed that the aromatic ring system, heterocyclic nitrogen containing compounds and amines are important for cholinesterase inhibition. Finally, the model was deployed as a publicly available webserver called the ABCpred at http://codes.bio/abcpred/.Graphic abstract

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.

Alkaloids are an important group of specialized nitrogen metabolites with a wide range of biochemical and pharmacological effects. Since the first publication on lycorine in 1877, more than 650 alkaloids have been extracted from Amaryllidaceae bulbous plants and clustered together as the Amaryllidaceae alkaloids (AAs) family. AAs are specifically remarkable for their diverse pharmaceutical properties, as exemplified by the success of galantamine used to treat the symptoms of Alzheimer’s disease. This review addresses the isolation, biological, and structure activity of AAs discovered from January 2015 to August 2020, supporting their therapeutic interest.

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.

Trillium govanianum is traditionally used to treat innumerable alignments like sexual disorders, cancer, inflammation etc. Mainly rhizomes of T. govanianum have been explored for phytochemical profiling but comprehensive metabolomics of other parts has not been yet deeply investigated. Thus, current study was aimed for organs-specific (roots, rhizomes, rhizomatous buds, stems, leaves, and fruits) phytochemical profiling of T. govanianum via metabolomics approach. Targeted (steroidal saponins and free sugars) and non-targeted metabolomics were performed by UPLC-PDA/ELSD & UHPLC-Q-TOF-IMS. Among steroidal compounds, 20-hydroxyecdysone, pennogenin-3-O- β -chacotrioside, dioscin were found predominantly in all samples while diosgenin was identified only in rhizomes. Further, four free sugars viz. 2-deoxyribose (116.24 ± 1.26 mg/g: leaves), fructose (454.76 ± 12.14 mg/g: rhizomes), glucose (243.21 ± 7.53 mg/g: fruits), and galactose (69.06 ± 2.14 mg/g: fruits) were found significant in respective parts of T. govanianum . Elemental analysis of targeted samples was determined by atomic absorption spectrophotometer. Heavy metals (Cd, Hg, Pd, As) were absent while micro- (Mn, Na, Zn, Cu) and macro- (Ca, Fe, Mg, K) elements were found in all samples. Furthermore, UHPLC-Q-TOF-IMS had identified 103 metabolites based on their mass fragmentation patterns and 839 were tentatively predicted using METLIN database. The multivariate statistical analysis showed organs specific clustering and variance of metabolites. Apart from this, extracts were evaluated for in vitro anticholinesterase activity, and found potentials inhibitors with IC 50 values 2.02 ± 0.15 to 27.65 ± 0.89 mg/mL and 3.58 ± 0.12 to 16.81 ± 2.48 mg/mL of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme, respectively. Thus, comprehensive metabolomics and anti-cholinesterase activity of different parts of T. govanianum would lay the foundation for improving medicinal importance and health benefits of T. govanianum.

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.

As the global population ages, there is an increasing research on managing neurodegenerative diseases that mainly affect the elderly. Honey is one of the natural products and functional foods widely studied for its neuroprotective properties. This review investigates honey’s effectiveness as a neuroprotective agent through in vitro, in vivo, and clinical research. The articles were browsed from three databases (PubMed, ScienceDirect, and Scopus) between the years of 2012 and 2022 using the keywords “honey” crossed with “neurodegenerative”. Out of the 16 articles, six in vitro, eight in vivo, one combination study, and one clinical intervention were compiled. Among the various types of honey studied, the Tualang and Thyme honey exhibited the highest antioxidant, anti-inflammatory, and anticholinesterase activity, leading to the prevention and management of multiple neurodegenerative diseases such as Alzheimer’s disease. The neuroprotective properties of honey are primarily attributed to its high polyphenol content, with quercetin and gallic acid being the most prominent. This review compiled considerable evidence of the anti-neurodegenerative properties of honey presented by in vitro and in vivo studies. However, more clinical intervention studies are required to support these findings further.

This study was aimed to investigate the phenolic profile of methanolic extract of Trifolium repens L. leaves using LC–HRMS and LC–DAD and its anti--cholinesterase and anti-oxidant activities. The n-Hexane (Tr.Hex), chloroform (Tr.Chf), ethanol (Tr.Et), methanol (Tr.Cme), and aqueous (Tr.Aq) extracts were tested for anti-cholinesterases and anti-oxidant potentials. Twenty-nine phenolic compounds were quantified and identified. The highest amount present were of tyrosol (11.1 mg/g), quercetin-3-glucuronide (5.36 mg/g), formononetin-7-glucoside (5.03 mg/g), quercetin-3-O-glucoside (4.71 mg/g), 3,4-di-O-caffeoylquinic acid (4.69 mg/g), formononetin-7-glucoside-acetate (4.29 mg/g), quercetin-3-O-glucoside (4.26 mg/g), and formononetin (3.64 mg/g). Tr.Chf and Tr.Et were most active against AChE, BChE, and free radicals. Tr.Chf exhibited IC50 of 15 and 21 µg/mL against AChE and BChE, respectively. In the anti-oxidant study, Tr.Chf showed IC50 of 42 and 25 µg/mL against ABTS and DPPH radicals, respectively. The current results of anti-cholinesterase and anti-radical studies on T. repens further signify its potential application in neurodegenerative disorders.Graphic abstract

The current study explored the chemical composition and biological activities of the essential oil and ethanol extract of S alvia lanigera collected from Libya. The ethanol extract obtained from the wild growing S . lanigera was evaluated for the chemical composition via high-performance liquid chromatography with diode-array detection (HPLC–DAD), which demonstrated phenolic and flavonoid contents. A total of 17 compounds, representing phenolic and flavonoid derivatives, have been identified. Besides, gas chromatography–mass spectrometry (GC–MS) analysis of the essential oil obtained from S. lanigera aerial parts identified 24 compounds, accounting for 99.33% of the oil, and the major components were characterized to be 1,8-cineole (27.28%), camphor (25.82%), α-pinene (7.71%), and α-terpineol (7.67%). The results indicated that the oil and ethanol extract exhibited marked radical scavenging capacity toward DPPH (2,2-diphenyl-1-picrylhydrazyl), with IC 50 values of 0.1337 and 0.6331 µg/mL, respectively. Further, the oil and ethanol extract demonstrated potent activity against ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), with IC 50 values of 0.17 and 0.0501 µg/mL, respectively. Moreover, S. lanigera oil inhibited more than 76% of the acetylcholinesterase enzyme activity, with an IC 50 value of 144 ± 1.04 µg/mL. The in vitro data showed that the ethanol extract has potential antidiabetic properties toward the α -glucosidase enzyme with an IC 50 value of 124.6 ± 1.07 µg/mL. Regarding the nature of measurement, assay conditions, and ligand-specific factors such as solubility and stability, we demonstrated a correlation between the IC 50 values and in-silico results for antidiabetic assays, where chlorogenic and rosmarinic acids recorded the highest docking scores of -9.4 and − 8.9 kcal/mol, respectively. However, this correlation was not observed in the anti-cholinesterase assay. Further in vivo investigations are essential to confirm the in vitro results of S. lanigera oil and ethanolic extract. This study helps elucidate the potential therapeutic applications of these compounds and their effectiveness in managing diabetes and neurodegenerative disorders.