Search Results (345)

Background/Objectives: Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative condition characterized by neurofibrillary tangles, neuronal loss, cognitive impairment, and accumulation of β-amyloid plaques. Considering the limitations of current treatments, which present adverse effects and only alleviate symptoms without modifying disease progression, there is an urgent need for new therapeutic approaches. This study aimed to investigate the neuroprotective potential of synthetic derivatives of (1E,4E)-1,5-bis[(het)aryl]penta-1,4-dien-3-ones, focusing on the inhibition of the cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets directly related to the cholinergic deficit observed in AD. Methods: The compounds were initially synthesized by aldol condensation reactions, with subsequent physicochemical characterization. They were then subjected to in silico assays that demonstrated high binding affinity to the active sites of AChE and BChE. The derivatives were evaluated in vitro for their inhibitory activity on these enzymes and in vivo in an experimental model of AD induced by streptozotocin in Wistar rats. Results: The synthesized derivatives showed favorable predicted interactions with the active sites of AChE and BChE, supporting their potential as cholinesterase inhibitors. In vitro assays demonstrated inhibitory activity against both enzymes, with selected derivatives showing improved activity compared with the parent scaffold. In the in vivo model, treatment with the selected compounds was associated with neuroprotective effects, suggesting preservation of nervous tissue integrity under AD-like conditions. Conclusions: These findings indicate that derivatives may represent promising candidates for further investigation as multitarget agents for AD. The study reinforces the relevance of integrating organic synthesis, molecular modeling, enzymatic assays, and in vivo evaluation in the search for new therapeutic strategies for neurodegenerative diseases. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that requires therapeutic agents capable of targeting multiple pathological pathways. In this study, a series of cannabidiol (CBD)-like hydrazone derivatives (3a–i) was synthesized and characterized by NMR, HRMS, and single-crystal X-ray diffraction for compound 3i. In silico ADME analysis predicted favorable drug-like properties, including compliance with Lipinski’s Rule of Five, oral bioavailability, and blood–brain barrier permeability. The compounds were evaluated for cholinesterase inhibition, antioxidant activity, cytotoxicity in neuronal cell lines, and binding interactions with human butyrylcholinesterase (hBChE) by molecular docking. Biological evaluation revealed a marked preference for BChE over acetylcholinesterase (AChE). Compound 3f was the most potent BChE inhibitor (IC₅₀ = 1.67 ± 0.11 μM), while compounds 3b and 3f demonstrated high selectivity toward BChE. Antioxidant assays (DPPH, ABTS, FRAP, and FTC) indicated moderate, mechanism-dependent activity. Compounds 3b and 3e showed the strongest ABTS radical-scavenging effects, whereas compounds 3b and 3f provided the greatest protection against lipid peroxidation, surpassing CBD under the tested conditions. Several derivatives, particularly 3a, 3b, 3f, 3h, and 3i, exhibited favorable safety profiles in SH-SY5Y and Neuro-2a cells. Molecular docking supported the experimental findings. Overall, compounds 3b and 3f emerged as promising multifunctional leads for the development of multitarget-directed anti-Alzheimer agents. Full article

Cholinesterase inhibitors with distinct pharmacological profiles may influence exploratory behavior, yet their effects on recall-related exploration in physiologically intact animals remain insufficiently characterized. The present study aimed to directly compare the effects of donepezil, a relatively selective acetylcholinesterase inhibitor, and tacrine, a cholinesterase inhibitor with broader enzymatic and pharmacological activity, on exploratory allocation during memory recall in healthy rats. Male Wistar rats were assigned to five groups (n = 8/group): control, donepezil 1 mg/kg, donepezil 3 mg/kg, tacrine 3 mg/kg, and tacrine 5 mg/kg. Treatments were administered intraperitoneally 50 min before the acquisition trial, while recall performance was evaluated 24 h later without additional treatment using a two-trial Y-maze paradigm. Time spent and entries into the familiar and novel arms, novel-to-familiar ratios, and mean time per entry were analyzed. Control animals showed no marked preference for the novel arm, whereas donepezil produced only limited, non-significant behavioral changes. Tacrine 5 mg/kg significantly increased the U/K time ratio compared with controls (p = 0.0006) and the U/K entry ratio (p = 0.001), primarily through reduced time spent in the familiar arm (p = 0.0004) and fewer familiar-arm entries (p = 0.025). Absolute time spent in, and entries into, the novel arm did not differ significantly among groups (p = 0.689 and p = 0.883, respectively). Overall, these findings suggest that tacrine, but not donepezil, modified recall-phase exploratory preference in healthy rats, predominantly by reducing persistence in the familiar arm. Full article

Background: Emergence delirium (ED) is a common complication in pediatric patients following general anesthesia. Reduced cholinergic neurotransmission is closely associated with cognitive impairment and an increased risk of delirium. This study aimed to compare the effects of a cholinesterase inhibitor versus sugammadex–used as neuromuscular blockade reversal agents–on the incidence of ED following pediatric strabismus surgery. Methods: Seventy-six patients, aged 4–7 years, were enrolled and randomly allocated to either the pyridostigmine group (Group P) or the sugammadex group (Group S). The dose of each agent was determined according to the train-of-four count or ratio. The Pediatric Anesthesia Emergence Delirium (PAED) scale was assessed at 15-min intervals in the post-anesthesia care unit until the score fell below 10. ED was defined as a PAED score ≥ 10. Results: Of the 73 patients who completed the study, 36 were in Group P, and 37 were in Group S. The incidence of ED was 50.0% in Group P and 40.5% in Group S (odds ratio = 0.682; 95% confidence interval = 0.270–1.721; p = 0.417). The peak PAED scores were 10.0 (7.0, 15.5) in Group P and 9.0 (7.5, 11.5) in Group S (median [interquartile range]; p = 0.277). Conclusions: The choice of neuromuscular reversal agent did not significantly affect the incidence of ED in pediatric patients undergoing strabismus surgery. Full article

Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer’s disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure–activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood–brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer’s disease. Full article

Thienopyrimidine derivatives are emerging as potent scaffolds for cholinesterase inhibition in Alzheimer’s disease therapy. In this work, a novel series of substituted thieno[2,3-d]pyrimidines was synthesized via Gewald’s reaction, followed by cyclization and functionalization through nucleophilic substitution and hydrazone formation. Structural confirmation was achieved using spectroscopic techniques, and biological evaluation was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil and rivastigmine as reference drugs. Compound 4 emerged as the most potent and selective AChE inhibitor (IC₅₀ = 0.58 µM), while compound 7 also showed strong AChE inhibition (IC₅₀ = 0.63 µM). Notably, compound 9 exhibited superior BChE inhibition (IC₅₀ = 3.05 µM) compared to donepezil (IC₅₀ = 8.41 µM). Dual inhibitory activity was observed for compounds 5, 6, and 11, highlighting their multitarget potential. Molecular dynamics simulations (200 ns) and MM/GBSA binding free energy calculations provided mechanistic insights. Compound 4 showed the most favorable binding energy (ΔGbind = −59.16 kcal/mol), driven by hydrogen bonds with Tyr121 and Glu199 and π-π stacking with Trp83. Residue-level decomposition identified Tyr121, Trp83, Glu199, and Tyr338 as critical contributors to binding stability. Structure–activity relationship analysis confirmed that nitrogen-containing substituents and cyclic amino moieties enhance potency, whereas bulky aromatic groups reduce activity. These findings establish thieno[2,3-d]pyrimidine derivatives as promising candidates for the development of next-generation anti-Alzheimer agents. Full article

Delirium is a transient neuropsychiatric condition that is a severe and prevalent condition affecting 2.6 million older adults each year. Alzheimer’s disease (AD) and anticholinergic medication use are risk factors for delirium. This study evaluated the association between cumulative anticholinergic burden (CAB) and risk of delirium among older adults with AD initiating cholinesterase inhibitors (ChEIs). This retrospective cohort study used 2013–2017 Medicare claims data, and included adults 65 years and older with AD who initiated any of the ChEIs (donepezil, rivastigmine, and galantamine) after a 12-month washout period. CAB, as the primary exposure, was measured on the index date and calculated as the monthly total standardized daily dose of anticholinergic medications. A multivariable Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) generated using generalized boosted models was used to evaluate the risk of delirium associated with the CAB. This study identified 143,320 older adults with AD who initiated ChEIs. Most patients were in the low/no burden (62.73%) group, followed by high burden (21.12%) and moderate burden (16.14%). Overall, delirium diagnosis was observed in 19.11% of the cohort. The Cox regression model with IPTW found that moderate (aHR, 1.56; 95% CI, 1.52–1.61; p < 0.0001) and high CAB (aHR, 1.45; 95% CI, 1.42–1.49; p < 0.0001) were associated with an increased risk of delirium compared to low/no burden. Among older adults with AD initiating ChEIs, moderate and high CAB were associated with an increased risk of delirium compared with low/no CAB. These findings highlight the need to carefully reduce the CAB, especially dose and duration, along with utilizing anticholinergic alternatives in older adults with AD. Full article

Artemisia campestris is a medicinal plant species endemic to Algeria, particularly abundant in the southern regions and the central Sahara. Its long-standing use in traditional medicine has recently gained scientific attention, prompting further investigation into its bioactive potential. This study focuses on the phytochemical composition and biological activity of its hydromethanolic extract, with a particular emphasis on its ability to inhibit neural enzymes associated with insect physiology with particular relevance to Aphis gossypii (Glover), a major polyphagous agricultural pest. Preliminary screening revealed a diverse array of secondary metabolites, including tannins (catechic and gallic), flavonoids, quinones, glycosides, terpenoids, saponins, coumarins, and alkaloids; however, anthocyanins were not detected. Quantitative analysis confirmed high concentrations of total phenolics (80.91 ± 1.58 mg GAE/g), flavonoids (60.45 ± 2.02 mg RE/g), phenolic acids (4.24 ± 0.38 mg CAE/g), and condensed tannins (2.26 ± 0.29 mg CE/g). Enzyme inhibition assays were performed using Ellman’s method, and IC₅₀ values were calculated by nonlinear regression analysis based on dose–response curves. The extract demonstrated significant in vitro inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀ values of 13.79 ± 0.79 µg/mL and 8.34 ± 0.58 µg/mL, respectively. Molecular docking analyses further confirmed strong binding affinities of cyanidin-3-O-glucoside, malvidin-3-O-glucoside, and apigenin (−8.20 to −8.50 kcal/mol) with the AChE active site, stabilized by hydrogen bonding and π–π interactions with key residues. These results were benchmarked against galantamine, a reference inhibitor, which exhibited IC₅₀ values of 1.50 ± 0.12 µg/mL under the same conditions. Although galantamine showed superior potency, the relatively low IC₅₀ values of the A. campestris extract support its potential as a natural cholinesterase-inhibitory agent warranting further investigation. These findings suggest that A. campestris may represent a promising source of natural cholinesterase inhibitors with potential relevance for eco-friendly insect control. These in vitro and in silico findings provide a mechanistic rationale warranting future in vivo bioassay validation against A. gossypii and related agricultural pests. Full article

Dementia, and more specifically Alzheimer’s disease (AD), is a progressive neurodegenerative disorder that has become a growing health menace in the world with an escalation in incidence as well as enormous social and economic consequences. Existing pharmacological treatment including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are not very effective in reducing the symptoms and fail to prevent the disease process. The non-pharmacological treatment interventions such as diet, exercise and cognitive training have supportive effects and cannot be used as standalone treatments. Therapeutic gap has resulted in increased interest in complementary and alternative therapies, especially that of pleiotropic action of herbal medicines. Bacopa monnieri (BM) is an Ayurvedic herb that has historically been used to treat memory enhancement and now has both preclinical and clinical evidence supporting its ability to modulate neurotransmission, reduce oxidative stress and suppress neuroinflammation. However, such difficulties as low bioavailability, instability of the environmental factors, and variations in formulations restrict its clinical applicability. New technologies with a lot of potential such as microencapsulation technology can provide the solution to this problem by increasing stability, solubility, and targeted delivery of compounds that will increase treatment efficacy. This narrative review is a synthesis of the existing information on the pathogenesis of dementia, therapeutic approaches, and the effectiveness of BM as a complementary intervention. It points out links between traditional medicine and modern neuroscience, strengths and limitations of on-going evidence, gaps that need further research, such as long-term clinical trials, standardized formulations, and discovery of the role of BM in the gut–brain axis. BM is a prime example of how herbal medicines can be used as a complement to conventional treatment and play a role in multi-modal approaches aimed at reducing the cognitive impairment associated with dementia. Full article

Alzheimer’s disease (AD) is a common neurodegenerative disorder linked to cholinergic dysfunction, with butyrylcholinesterase (BChE) being a key therapeutic target for moderate–severe AD. Cortex Mori Radicis, a traditional Chinese medicinal herb, is rich in Diels–Alder adducts with potential neuroprotective effects; here, eighteen Diels–Alder adducts (four new: morusalbanol B–E, 1–4) were isolated and identified from its 80% ethanol extract. Their cholinesterase inhibitory activities were assessed via Ellman’s method, with enzyme kinetics and molecular docking performed for active compounds. Most compounds showed selective BChE inhibition, with kuwanon X (14) being the most potent (IC₅₀ = 2.3 μM). morusalbanol B (1), cathayanon A (8), and kuwanon G (12) acted as noncompetitive inhibitors, while Morusalbanol C (2) and kuwanon X (14) were mixed competitive inhibitors. Molecular docking suggested that potent inhibitors occupied the BChE active pocket via hydrogen bonds, π-π stacking, and hydrophobic interactions with Trp82, His438, and Phe329. MD simulations and MM-GBSA binding free energy analysis further verified that all three representative complexes (1, 8, and 14) achieved favorable thermodynamic and structural stability, with binding driven primarily by van der Waals forces. Residue decomposition revealed that Trp82 and Phe329 served as core binding hotspots for all tested inhibitors. Structure–activity analysis indicated that a cis-trans methylcyclohexene configuration, shorter aliphatic ester chains, and more prenyl groups enhanced BChE inhibition. This study provides new lead compounds and a systematic molecular mechanism basis for developing novel anti-AD BChE inhibitors from natural products. Full article

A novel series of hybrid tetrahydro-β-carboline (THβC)-imidazolium (IM) salts incorporating a fused diketopiperazine scaffold was designed, synthesized, and evaluated as cholinesterase inhibitors for potential application in Alzheimer’s disease. The molecular design integrates a π-conjugated THβC core with a cationic IM moiety to promote dual-site interactions within the acetylcholinesterase (AChE) active-site gorge. All compounds exhibited micromolar inhibitory activity against AChE and butyrylcholinesterase (BChE), with a pronounced preference for AChE. The most active derivative, 12d, showed an IC₅₀ value of 0.72 μM toward AChE, while compound 12c demonstrated the highest selectivity (SI = 8.4). Structure–activity relationship studies revealed that both stereochemistry and N-alkyl chain length are critical determinants of activity, with S,S-configured derivatives consistently outperforming their R,R-configured analogs. In silico ADMET analysis indicated favorable physicochemical properties and predicted central nervous system permeability, although potential hepatotoxicity highlights the need for further optimization. Molecular docking studies suggested that the most promising compound adopts a dual-binding mode, interacting with both the peripheral anionic site and catalytic active site of AChE. These results identify THβC-IM hybrids as a structurally novel and promising scaffold for the development of selective cholinesterase inhibitors, providing a basis for further optimization toward multifunctional anti-Alzheimer agents. Full article

Neurodegenerative diseases are a serious problem for modern society, and their treatment remains an important issue discussed by the scientific community. One of the promising potential directions for modulating neurodegenerative processes is the use of acylhydrazones, a class of compounds that combine different bioactive fragments linked by an acylhydrazone moiety. So far, the biological properties of these compounds have been proven. They show antibacterial, antiviral, antifungal, antiparasitic, anticancer, anti-inflammatory and antioxidant activity. Many research papers focus on designing acylhydrazones that will find use in the treatment of neurodegenerative diseases by inhibiting the enzymatic activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase 1 (BACE1) and monoamine oxidase (MAO), as well as inhibiting β-amyloid aggregation, exhibiting metal chelation and antioxidant properties. Recent studies have described the acylhydrazone-based dual (multi-target) inhibitors, which have demonstrated encouraging outcomes during in vitro evaluations. This review covers recent articles published in the years 2020–2025 and offers a comprehensive overview of the biological properties of the acylhydrazones and their multifunctional derivatives on neurodegenerative processes and/or neuroprotection, while emphasizing their universal nature, structural versatility and role as leading structures in the search for new drugs. Full article

Ten substituted quinobenzothiazinium salts were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All the compounds inhibited AChE in the IC₅₀ range of 0.03–0.658 µM, with 5,8,10-trimethyl-12H-quinolino[3,4-b][1,4]benzothiazin-5-ium chloride (3d) being the most potent inhibitor, with an IC₅₀ value significantly better than that of the clinically used rivastigmine and galantamine and comparable to that of tacrine and donepezil. The IC₅₀ values for BChE inhibition ranged from 0.34 to 4.25 µM; 5,9-dimethyl-12H-quinolino[3,4-b][1,4]benzothiazin-5-ium chloride (3b) exhibited the strongest BChE inhibitory activity and in general, all the investigated compounds were more potent inhibitors than rivastigmine and galantamine. Based on the calculated selectivity index values, they are rather preferential inhibitors of AChE. Cytotoxicity tests performed on normal human dermal fibroblasts (HFF-1) did not demonstrate any significant cytotoxicity under the tested conditions. The distance-oriented structure distribution for the studied molecules was related with the activity data using principal component analysis and hierarchical clustering analysis. (SAR)-based evaluation is reported to predict activity cliffs using a similarity–activity landscape index for the AChE inhibitory response values. Moreover, direct protein-mediated in silico methods were utilized to identify factors that may be relevant for quantitative (Q)SAR modeling. In practice, target-oriented molecular docking was used to organize the spatial distribution of the ligand property space for the anti-AChE system. In general, this series of alkylated quinobenzothiazinium salts with potent inhibitory activity against cholinesterases fulfills Lipinski’s rule of five based on in silico predictions and is also expected to have high absorption in the human gastrointestinal tract. All active derivatives are also expected to penetrate the blood–brain barrier, making them promising compounds for further research and possible use in Alzheimer’s disease therapy. Full article

Lippia origanoides Kunth (Verbenaceae family), popularly known in northern Brazil as “Salva-de-Marajó”, is a native plant widely used in traditional medicine and cooking. While previous studies have addressed its antimicrobial and insecticidal properties, its ability to inhibit disease-related enzymes has received limited attention. This study investigated the essential oil (EO) of L. origanoides as a source of enzyme inhibitors relevant to Alzheimer’s disease, metabolic disorders and skin pigmentation disorders. The EO showed strong inhibitory activity against acetylcholinesterase (IC₅₀: 22.9 μg/mL) and α-glucosidase (IC₅₀: 14.6 μg/mL), indicating potential for managing neurodegenerative conditions and diabetes, respectively. Moderate inhibition was observed for lipase, butyrylcholinesterase and tyrosinase. Although carvacrol, the major EO constituent, contributed significantly to these effects, it did not fully explain the observed bioactivity. Bio-guided fractionation revealed that oxygenated compounds were mainly responsible for inhibiting cholinesterases and lipase, whereas α-glucosidase inhibition was associated with hydrocarbon compounds. Both fractions contributed to tyrosinase inhibition, reinforcing the EO’s relevance for treating hyperpigmentation. Furthermore, the EO demonstrated strong antioxidant activity, largely linked to carvacrol and oxygenated constituents. Chemical characterization by GC-MS, GC-FID and enantiomeric analysis strengthened the relationship between composition and bioactivity. Overall, L. origanoides EO emerged as a promising multifunctional natural product for therapeutic and cosmetic applications. Full article

Alzheimer’s disease (AD) remains a significant global health challenge, highlighting the need for novel dual inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This study investigated the trunk bark of Terminalia triptera Stapf. as a potential source of bioactive secondary metabolites for AD management. Bioassay-guided isolation led to the identification of two flavan-3-ol derivatives, epicatechin-(4β→8)-ent-catechin (1) and (−)-catechin (2), reported here for the first time from this species. In vitro assays demonstrated that the dimeric compound 1 exhibited stronger dual inhibitory activity against AChE and BChE, with IC₅₀ values of 4.41 × 10⁻⁴ and 4.75 × 10⁻⁴ mol/L, respectively, surpassing the reference compound berberine chloride. Molecular docking analysis revealed that compound 1 formed extensive interactions within both catalytic and peripheral anionic sites of the enzymes. Density Functional Theory (DFT) calculations indicated high kinetic stability, reflected by large HOMO–LUMO energy gaps (6.66–6.97 eV), while global reactivity descriptors suggested lower electrophilicity (ω = 2.19–2.34 eV), supporting a potentially favorable safety profile. Furthermore, 100 ns molecular dynamics simulations confirmed stable ligand–protein complexes stabilized by hydrogen-bond networks and deep binding within catalytic pockets. Overall, these findings highlight T. triptera and its dimeric proanthocyanidins as promising multi-target candidates for anti-Alzheimer drug development. Full article