anti-Alzheimer's Disease Research Articles

Anti-Alzheimer's Disease Target and Beneficial Effect in Formononetin

Introduction: Alzheimer's Disease (AD), a common neurodegenerative relevance of dementia, is spreading in the world. Hitherto, the pharmacological treatment for AD is prescribed limitedly in clinical application. Recently, it has been found that naturally occurring extracts possess promising anti-neurodegenerative properties, including AD. Method: Our previous study indicated that formononetin (FMN) exerts the anti-AD benefits based on bioinformatics analysis. However, the experimental validation for bioinformatics findings has not been conducted. In this study, we primarily applied the molecule docking analysis to ascertain the pharmacological targets, including cytochrome P450 19A1 (CYP19A1). Transgenic AD mice were used to validate the bioinformatics findings in vivo experimentally. Molecular docking data showed that FMN acted directly on CYP19A1 target protein with effective binding sites and potent combining affinity/energy. Results: Meanwhile, FMN intervention contributed to an increased trend of body weight in transgenic AD mice reduced hippocampal expression of Aβ1-42, and elevated content of CYP19A1. Additionally, FMN intervention showed reduced terminal deoxynucleotidyl Transferase dUTP Nick-End Labeling (TUNEL) expression and increased CYP19A1 and Ki67 expressions in hippocampal sections of transgenic AD mice. Conclusion: Collectively, FMN may be used for the prevention of AD, and the pharmacological activities are possibly related to reducing Aβ1-42, and TUNEL expressions to increase Ki67 and CYP19A1 activities.

Usnic Acid Derivatives as Multi-Target Anti-Alzheimer's Disease Agents: Design, Synthesis, X-Ray Single Crystal Structure of Zn(II) Complex and Biological Activities.

Alzheimer's disease (AD) is multifactorial, which makes the design of multi-target-directed ligands an attractive strategy for the development of anti-AD drugs. In order to enhance the anti-AD effects and reduce the toxicity, two usnic acid (UA) derivatives (1-2) were designed, synthesized and fully characterized by introducing dimethylamine Schiff base moiety into the toxic "triketone" portion. Ellman's method and molecular docking were used to test the cholinesterase inhibitory activities. Antioxidant activities were studied with Fenton reaction, cyclic voltammetry and C. elegans. The results showed that compared with UA, 1-2 had stronger anti-cholinesterase activities and similar antioxidant activities. Notably, solvent evaporation of 2 and ZnCl2 formed a single crystal, which was revealed to be a Zn(II) complex with UA and tertiary amine as mixed ligands by X-ray diffraction. The hydrolysis of 2 was thus furtherly studied by HPLC. Furthermore, the crystal structure supported the replacement of toxic "triketone" moiety in the chelation process, playing a detoxifying role and at the same time regulating metal homeostasis. In silico prediction also showed low hepatotoxicity and acceptable drug-likeness of 1-2. Overall, this work provided useful insights into multi-target anti-AD candidates with the natural product UA as the lead compound.

Biosynthesis and biological activities of magnesium hydroxide nanoparticles using Tinospora cordifolia leaf extract.

The synthesis of magnesium hydroxide nanoparticles (Mg(OH)2 NPs) using plant extracts are known to be a practical, economical, and an environmentally friendly approach. In this work, Mg(OH)2 NPs were synthesized using aqueous leaf extract of Tinospora cordifolia, a medicinal plant commonly found in India. The synthesized Mg(OH)2 NPs were characterized using various spectroscopic techniques. The ultraviolet-visible (UV-Vis) absorption peak of the Mg(OH)2 NPs was detected at 289nm, Fourier transform infrared (FTIR) analysis confirmed the presence of various functional groups, and X-ray diffraction (XRD) patterns revealed the well-crystallized structure of the Mg(OH)2 NPs. High-resolution transmission electron microscopy (HR-TEM) and scanning electron microscopy (SEM) analyses depicted spherical morphology and an average particle size (PS) of 27.71nm. The energy-dispersive X-ray (EDX) analysis confirmed the presence of C, O, and Mg elements, and the X-ray photoelectron spectroscopy (XPS) survey spectrum confirmed the elements for the Su 1s peak at 280.2eV. The dynamic light scattering (DLS) analysis displayed an average PS of 54.3nm, and the Zeta potential (ZP) was of 9.89mV. The fabricated Mg(OH)2 NPs displayed notable antibacterial activity against S. epidermidis, E. coli, and S. aureus. In addition, these NPs exhibited strong antioxidant properties (> 75%) based on DPPH, ABTS, and hydrogen peroxide (H2O2) assays. Further, the same NPs exerted a potent anti-inflammatory activity (> 65%) based on COX-1 and COX-2 evaluations. The anti-Alzheimer' disease (AD) potential of Mg(OH)2 NPs was assessed through effective inhibition (> 70%) of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities. Molecular docking (MD) studies confirmed that caryophyllene has higher binding affinity with AChE (-5.3kcal/mol) and BuChE (-6.4kcal/mol) enzymes. This study emphasizes the green synthesis of Mg(OH)2 NPs using T. cordifolia as a plant source and highlights their potential for biomedical applications.

Network pharmacology-based mechanism analysis of dauricine on the alleviating Aβ-induced neurotoxicity in Caenorhabditis elegans

BackgroundDauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, exhibits promising anti-Alzheimer’s disease (AD) effects, but its underlying mechanisms remain inadequately investigated. This paper aims to identify potential targets and molecular mechanisms of DAU in AD treatment.MethodsNetwork pharmacology and molecular docking simulation method were used to screen and focus core targets. Various transgenic Caenorhabditis elegans models were chosen to validate the anti-AD efficacy and mechanism of DAU.ResultsThere are 66 potential DAU-AD target intersections identified from 100 DAU and 3036 AD-related targets. Subsequent protein-protein interaction (PPI) network analysis identified 16 core targets of DAU for anti-AD. PIK3CA, AKT1 and mTOR were predicted to be the central targets with the best connectivity through the analysis of “compound-target-biological process-pathway network”. Molecular docking revealed strong binding affinities between DAU and PIK3CA, AKT1, and mTOR. In vivo experiments demonstrated that DAU effectively reduced paralysis in AD nematodes caused by Aβ aggregation toxicity, downregulated expression of PIK3CA, AKT1, and mTOR homologues (age-1, akt-1, let-363), and upregulated expression of autophagy genes and the marker protein LGG-1. Simultaneously, DAU increased lysosomal content and enhanced degradation of the autophagy-related substrate protein P62. Thioflavin T（Th-T）staining experiment revealed that DAU decreased Aβ accumulation in AD nematodes. Further experiments also confirmed DAU’s protein scavenging activity in polyglutamine (polyQ) aggregation nematodes.ConclusionCollectively, the mechanism of DAU against AD may be related to the activation of the autophagy-lysosomal protein clearance pathway, which contributes to the decrease of Aβ aggregation and the restoration of protein homeostasis.

Neuroprotective Effects of Phenolic Constituents from Drynariae Rhizoma.

This study aimed to provide scientific data on the anti-Alzheimer's disease (AD) effects of phenolic compounds from Drynariae Rhizoma (DR) extract using a multi-component approach. Screening of DR extracts, fractions, and the ten phenolic compounds isolated from DR against the key AD-related enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and monoamine oxidase-B (MAO-B) confirmed their significant inhibitory activities. The DR extract was confirmed to have BACE1-inhibitory activity, and the ethyl acetate and butanol fractions were found to inhibit all AD-related enzymes, including BACE1, AChE, BChE, and MAO-B. Among the isolated phenolic compounds, compounds (2) caffeic acid 4-O-β-D-glucopyranoside, (6) kaempferol 3-O-rhamnoside 7-O-glucoside, (7) kaempferol 3-o-b-d-glucopyranoside-7-o-a-L-arabinofuranoside, (8) neoeriocitrin, (9) naringin, and (10) hesperidin significantly suppressed AD-related enzymes. Notably, compounds 2 and 8 reduced soluble Amyloid Precursor Protein β (sAPPβ) and β-secretase expression by over 45% at a concentration of 1.0 μM. In the thioflavin T assay, compounds 6 and 7 decreased Aβ aggregation by approximately 40% and 80%, respectively, and degraded preformed Aβ aggregates. This study provides robust evidence regarding the potential of DR as a natural therapeutic agent for AD, highlighting specific compounds that may contribute to its efficacy.

Design, synthesis and anti-Alzheimer's disease activity evaluation of C-3 arylated huperzine A derivatives

A series of C-3 arylated huperzine A (HPA) derivatives (1−30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC50 = 1.205 ± 0.395 μM; 15, IC50 = 0.225 ± 0.062 μM) and butyrylcholinesterase (BChE inhibition: 2, IC50 = 8.598 ± 3.605 μM; 15, IC50 = 4.013 ± 0.068 μM), a feature not observed in huperzine A. Molecular docking results indicated that the introduction of aryl groups enhanced the affinity of the derivatives for the acyl-binding pocket of BChE, thereby limiting the hydrolysis of acetyl choline. However, these derivatives exhibited poor performance in cytotoxicity and neuroprotection assays.

Assessment of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer’s disease: A population-based study

The lack of effective treatments for dementia has led to explore the potential of antidiabetic agents as a possible approach. This cross-sectional and population-based study aimed to investigate the relationship between each antidiabetic drug and their defined daily doses (DDDs) and the use of anti-Alzheimer’s disease (AD) drugs in order to establish new possible hypotheses about the role of antidiabetic drugs in AD.For that purpose, a database containing information on medications prescribed to 233183 patients aged 50 years or older between 2018 and 2020 was used. DDDs were calculated according to the ATC/DDD index 2023. Statistical analyses, with logistic regression, were carried out to assess antidiabetic and anti-AD drugs consumption.A total of 91836 patients who were prescribed at least one antihypertensive, antidiabetic, or lipid-modifying agent were included in the study; specifically, 29260 patients were prescribed antidiabetic medication. Among the antidiabetic agents, glucagon–like peptide–1 analogs (GLP–1) DDDs were likely to have a positive association with anti-AD drugs in people aged between 70 and 80 years. Additionally, sodium–glucose cotransporter 2 inhibitors (SGLT2i) were prone to have a positive association with anti-AD drug usage across almost every age. However, insulin usage was associated with an increased usage of anti-AD agents.In conclusion, there is evidence suggesting a correlation between certain antidiabetic agents and dementia. Specifically, GLP-1 and SGLT2i might be associated with lower odds of anti-AD drugs usage, while insulins might be linked to higher odds of using anti-AD drugs.

4D-QSAR, ADMET properties, and molecular dynamics simulations for designing N-substituted urea/thioureas as human glutaminyl cyclase inhibitors

Human glutaminyl cyclase (hQC) inhibitors have great potential to be used as anti- Alzheimer's disease (AD) agents by reducing the toxic pyroform of β-amyloid in the brains of AD patients. The four-dimensional quantitative structure activity relationship (4D-QSAR) model of N-substituted urea/thioureas was established with satisfying predictive ability and statistical reliability (Q2 = 0.521, R2 = 0.933, R2prep = 0.619). By utilizing the developed 4D-QSAR model, a set of new N-substituted urea/thioureas was designed and evaluated for their Absorption Distribution Metabolism Excretion and Toxicity (ADMET) properties. The results of molecular dynamics (MD) simulations, Principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM) and molecular mechanics generalized Born Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, revealed that the designed compounds were remained stable in protein binding pocket and compounds b ∼ f (−35.1 to −44.55 kcal/mol) showed higher binding free energy than that of compound 14 (−33.51 kcal/mol). The findings of this work will be a theoretical foundation for further research and experimental validation of urea/thiourea derivatives as hQC inhibitors.

Comprehensive profiling of acetylcholinesterase inhibitors from fried centipede using activity-oriented online preparation technology

Fried centipede, a popular food in southern China and Vietnam, is well known for its notable health benefits owing to its unique chemical composition. This study focused on acetylcholinesterase (AChE) inhibitor screening, bioactivity evaluation, and the extraction of bioactive compounds derived from fried centipedes. To determine the accuracy of in vitro AChE inhibitor screening, receptor-ligand affinity ultrafiltration and enzymatic reaction kinetics technologies were employed for the rapid screening and structural identification of bioactive compounds and to verify the enzyme inhibition activity and mechanism of the compounds. Moreover, molecular docking and dynamic simulations were utilized to assess the effectiveness of the target, and the integration of experimental and computational approaches facilitated a comprehensive analysis of the active compounds and their activities at four levels. To address the issues of low content and low extraction and separation efficiencies of bioactive compounds derived from centipedes, an activity-oriented complex preparation method (consecutive ultrasonic-assisted centrifugal extraction coupled online with UNIFAC countercurrent chromatography and semi-high-performance liquid chromatography (HPLC) was developed for efficient extraction, online concentration, and complex separation of the identified AChE ligands. As a result, six active compounds, including cytidine, guanine, uracil, hypoxanthine, xanthine, and β-thymidine demonstrated significant binding affinity to the AChE active sites within 3 h. This study provided valuable insights into the active compounds of fried centipedes and their potential anti-Alzheimer's disease properties. These findings contribute to the advancement of animal food preparation methodologies by combining cutting-edge extraction techniques, biological activity screening, and the development of AChE inhibitors from fried centipedes. Our method serves as a valuable reference for exploring and developing functional animal materials from diverse medicinal resources.

Phenolic content of Thai Bao mango peel and its in-vitro antioxidant, anti-cholinesterase, and antidiabetic activities

Plant phenolics have been known for various biological activities. This study aims to extract and examine the presence of phenolics in Bao mango (Mangifera indica L. var.) peel ethanolic extract (MPE). Further, antioxidant, anti-diabetic (α-amylase, and α-glucosidase inhibitory activity), and anti- Alzheimer’s disease (AD) (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) inhibitory activity) efficacy of MPE were determined. The results indicated that mangiferin (8755.89 mg/ 100 g extract) was the major phenolic compound in MPE. An antioxidant mechanism revealed that MPE had a higher radical scavenging ability (4266.70 µmol TE/g extract) compared to reducing power (FRAP) or oxygen radical absorption capacity (ORAC). Further in-vitro enzyme inhibitory assay against diabetic and AD involved enzymes showed that MPE had stronger inhibitory action against an enzyme involved in diabetes compared to their standard drug (Acarbose) (P < 0.05). While a lower IC50 value was observed against AD-involved enzymes compared to their standard drug (donepezil) (P < 0.05). The results show that Thai Bao mango peel byproduct can be a potential source of nutraceuticals to lower diabetes and improve cognitive health.

Box-Behnken Design-Based Optimization of Phytochemical Extraction from Diplazium esculentum (Retz.) Sw. Associated with Its Antioxidant and Anti-Alzheimer's Properties.

A previous study reported that the ethanolic extract of the edible fern, Diplazium esculentum (Retz.) Sw. (DE), obtained from a non-optimized extraction condition exhibited anti-Alzheimer's disease (AD) properties through the inhibition of a rate-limiting enzyme in amyloid peptide formation, β-secretase-1 (BACE-1). Nevertheless, a non-optimized or suboptimal extraction may lead to several issues, such as a reduction in extraction efficiency and increased time and plant materials. In this study, extraction of the DE was optimized to obtain appropriate BACE-1 inhibition using a Box-Behnken design (BBD) and response surface methodology (RSM). Data revealed that the optimal extraction condition was 70% (v/v) aqueous ethanol, 50 min extraction time, 30 °C extraction temperature, and 1:30 g/mL solid/liquid ratio, giving BACE-1 inhibition at 56.33%. In addition, the extract also exhibited significant antioxidant activities compared to the non-optimized extraction. Metabolomic phytochemical profiles and targeted phytochemical analyses showed that kaempferol, quercetin, and their derivatives as well as rosmarinic acid were abundant in the extract. The optimized DE extract also acted synergistically with donepezil, an AD drug suppressing BACE-1 activities. Data received from Drosophila-expressing human amyloid precursor proteins (APPs) and BACE-1, representing the amyloid hypothesis, showed that the optimized DE extract penetrated the fly brains, suppressed BACE-1 activities, and improved locomotor functions. The extract quenched the expression of glutathione S transferase D1 (GSTD1), inositol-requiring enzyme (IRE-1), and molecular chaperone-binding immunoglobulin (Bip), while donepezil suppressed these genes and other genes involved in antioxidant and endoplasmic reticulum (ER) stress response, including superoxide dismutase type 1 (SOD1), activating transcription factor 6 (ATF-6), and protein kinase R-like endoplasmic reticulum kinase (PERK). To sum up, the optimized extraction condition reduced extraction time while resulting in higher phytochemicals, antioxidants, and BACE-1 inhibitors.

Lathyrane and premyrsinane Euphorbia diterpenes against Alzheimer's disease: Bioinspired synthesis, anti-cholinesterase and neuroprotection bioactivity

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1–32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 μM. Molecular docking demonstrated that 17 could bond with AChE well (−8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 μM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.

Novel multifunctional tacrine-donepezil hybrids against Alzheimer's disease: Design synthesis and bioactivity studies.

A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine-donepezil hybrids also exhibited significant neuroprotection against H2O2-induced cell death in a differentiated human neuroblastoma (SH-SY5Y) cell line at concentrations close to their IC50 values on ChEs and showed high to medium blood-brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC-5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH-SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine-donepezil scaffold represents a promising starting point for the development of novel anti-ChE multifunctional agents against AD.

Sulfonamide Derivatives: Recent Compounds with Potent Anti-alzheimer's Disease Activity.

Facile synthetic procedures and broad spectrum of biological activities are special attributes of sulfonamides. Sulfonamide derivatives have demonstrated potential as a class of compounds for the treatment of Alzheimer's disease (AD). Recent sulfonamide derivatives have been reported as prospective anti-AD agents, with a focus on analogues that significantly inhibit the function of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and exhibit remarkable antioxidant and anti-inflammatory properties, all of which are critical for the treatment of AD. Sulfonamide- mediated activation of nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the endogenous antioxidant response, has also been suggested as a potential therapeutic approach in AD. Additionally, it has been discovered that a number of sulfonamide derivatives show selectivity for the β- and γ-secretase enzymes and a significant reduction of amyloid B (Aβ) aggregation, which have been implicated in AD. The comparative molecular docking of benzenesulfonamide and donepezil, an AD reference drug showed comparable anti-AD activities. These suggest that sulfonamide derivatives may represent a new class of drugs for the treatment of AD. Thus, the current review will focus on recent studies on the chemical synthesis and evaluation of the anti-AD properties, molecular docking, pharmacological profile, and structure-activity relationship (SAR) of sulfonamide derivatives, as well as their potential anti-AD mechanisms of action. This paper offers a thorough assessment of the state of the art in this field of study and emphasizes the potential of sulfonamide derivatives synthesized during the 2012-2023 period as a new class of compounds for the treatment of AD.

Lemneolemnanes A-D, Four Uncommon Sesquiterpenoids from the Soft Coral Lemnalia sp.

Four undescribed sesquiterpenoids, lemneolemnanes A-D (1-4), have been isolated from the marine soft coral Lemnalia sp. The absolute configurations of the stereogenic carbons of 1-4 were determined by single-crystal X-ray crystallographic analysis. Compounds 1 and 2 are epimers at C-3 and have an unusual skeleton with a formyl group on C-6. Compound 3 possesses an uncommonly rearranged carbon skeleton, while 4 has a 6/5/5 tricyclic system. Compound 1 showed significant anti-Alzheimer's disease (AD) activity in a humanized Caenorhabditis elegans AD pathological model.

Green tea hydroxycinnamoylated catechins extend lifespan and attenuate Aβ-induced paralysis of Caenorhabditis elegans via anti-oxidation and peptides dis-aggregation

Hydroxycinnamoylated catechins (HCCs) could attenuate H2O2 or β-amyloid peptides (Aβ) induced damage in neural cells, thus having anti-Alzheimer's disease (AD) potential. Longjing43 green tea harvested in summer and autumn (LJ43-SA) has high HCCs content. We explored the anti-AD potential of the LJ43-SA together with common catechins and HCCs in green tea. Transgenic Caenorhabditis elegans (C. elegans) CL4176, CL2331, and CL2355 were used to explore the anti-AD effects. LJ43-SA prolonged the lifespan of paralytic nematodes and delayed the occurrence of paralysis. Tea catechins prolonged the lifespan (100 μM epigallocatechin 3-O-p-coumaroate (EGC-pC), 44% promotion) and healthspan of paralytic C. elegans, improving stress resistance, reducing ROS levels, MDA contents and Aβ deposition, enhancing GSH-Px and SOD activities, reinstating benzaldehyde chemotaxis (100 μM EGC-pC, 270% promotion), reducing 5-HT sensitivity (100 μM EGC-pC, 231% promotion), and alleviating glutamate-induced neurotoxicity (100 μM EGC-pC, 184% promotion). These results suggest that green tea extract and HCCs have anti-AD potential.

Integrated UHPLC-Q-Orbitrap-MS/MS Method and Network Pharmacology for Exploring the Active Components and Potential Mechanisms of Neuroprotective Effect of the n-Butanol Part of Mume Flos

Background: Mume Flos is a common Qi-regulating medication used in traditional Chinese medicine, modern study has discovered that Mume Flos and its components have neuroprotective properties. However, the effective components and molecular mechanisms of Mume Flos are still unclear. Methods: In this study, the current study chose Caenorhabditis elegans as a model to evaluate the anti-Alzheimer disease (AD) effect of the active parts of Mume Flos using life span, paralysis rate, oxidative stress capacity, and heat stress capacity as indicators. Then, UHPLC-Q-Orbitrap-MS/MS and network pharmacology combined with GEO database chip were used for joint analysis to predict the active components and potential molecular mechanisms, which were validated using C. elegans models. Results: The results showed that the n-butanol part of Mume Flos slowed down nematode paralysis and possessed anti-AD activity, and we tentatively identified a total of 45 constituents, mainly including flavonoids and phenylpropanoids as well as a small number of amino acids, and determined that 39 active components and 130 targets are related to neuroprotection. Further analysis identified the main active ingredients such as rutin, neochlorogenic acid, and chlorogenic acid, all of which could reduce Aβ deposition in nematodes and slow down the rate of paralysis in transgenic nematodes. Conclusion: This study revealed the neuroprotective effects of MFB and identified its active components as rutin, neochlorogenic acid, and chlorogenic acid. They may play a role in reducing Aβ deposition by regulating the targets of GAPDH, TNF, IL6, INS, and TP53. This study provides a basis for further in-depth research on the mechanism of MFB to improve neurological diseases.

Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study

Simple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from 117.5 to 455 nM for AChE and 34 to 324 nM for BuChE. As a representative of the series with the best cytotoxicity / ChE inhibitory activity ratio, expressed as the selectivity index (SI), 2-chlorobenzoyl derivative demonstrated mixed-type inhibition on AChE and BuChE, suggesting binding to both CAS and PAS of the enzymes. It also exhibited antioxidant capacity and neuroprotective potential against amyloid-β (Aβ) toxicity in the culture of neuron-like cells. In-depth computational analysis corroborated well with in vitro ChE inhibition, illuminating that all compounds exhibit significant potential in targeting both enzymes. Molecular dynamics (MD) simulations revealed that 2-chlorobenzoyl derivative, created complexes with AChE and BuChE that demonstrated sufficient stability throughout the observed MD simulation. Computationally predicted ADME properties indicated that these compounds should have good blood–brain barrier (BBB) permeability, an important factor for CNS-targeting drugs. Overall, all tested compounds showed promising pharmacological behavior, highlighting the multi-target potential of 2-chlorobenzoyl derivative which should be further investigated as a new lead in the drug development process.

Novel Flavonol Alkaloids in Green Tea: Synthesis, Detection, and Anti-Alzheimer's Disease Effect in a Transgenic Caenorhabditis elegans CL4176 Model.

Novel N-ethy-2-pyrrolidinone-substituted flavonols, myricetin alkaloids A-C (1-3), quercetin alkaloids A-C (4a, 4b, and 5), and kaempferol alkaloids A and B (6 and 7), were prepared from thermal reaction products of myricetin, quercetin, kaempferol─l-theanine, respectively. We used HPLC-ESI-HRMS/MS to detect 1-7 in 14 cultivars of green tea and found that they were all present in "Shuchazao," "Longjing 43", "Fudingdabai", and "Zhongcha 108" green teas. The structures of 1-4 and 6 were determined by extensive 1D and 2D NMR spectroscopies. These flavonol alkaloids along with their skeletal flavonols were assessed for anti-Alzheimer's disease effect based on molecular docking, acetylcholinesterase inhibition, and the transgenic Caenorhabditis elegans CL4176 model. Compound 7 strongly binds to the protein amyloid β (Aβ1-42) through hydrogen bonds (BE: -9.5 kcal/mol, Ki: 114.3 nM). Compound 3 (100 μM) is the strongest one in significantly extending the mean lifespan (13.4 ± 0.5 d, 43.0% promotion), delaying the Aβ1-42-induced paralysis (PT50: 40.7 ± 1.9 h, 17.1% promotion), enhancing the locomotion (140.0% promotion at 48 h), and alleviating glutamic acid (Glu)-induced neurotoxicity (153.5% promotion at 48 h) of CL4176 worms (p < 0.0001).

Design, synthesis, and biological evaluation of 1,2,4-oxadiazole-based derivatives as multitarget anti-Alzheimer agents.

A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds 2b, 2c, 2d, 3a, 4a, 6, 9a, 9b, and 13b showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC50 values in the range of 0.0158 to 0.121 μM. They were 1.01 to 7.78 times more potent than donepezil (IC50 = 0.123 μM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds 4b and 13b showed the most prominent inhibitory potential against BuChE with IC50 values of 11.50 and 15 μM, respectively. Moreover, 4b, and 9b were found to be more potent antioxidant agents (IC50 values of 59.25, and 56.69 μM, respectively) in comparison with ascorbic acid (IC50 = 74.55 μM). Compounds 2b and 2c exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC50 values of 74.68 and 225.48 μM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC50 = 265.85 μM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives 2c and 3a as multitarget anti-AD agents. The predicted ADME properties for compounds 2b and 4a were satisfactory, and 4a had the highest likelihood of crossing the blood-brain barrier (BBB), making it the optimum compound for future optimization.