Search Results (470)

Background/Objectives: The identification of acetylcholinesterase (AChE) inhibitors from complex natural matrices remains challenging due to the limitations of conventional colorimetric assays. This study aimed to develop a fluorescence-based AChE inhibition assay (FAIA) suitable for screening plant extracts, while simultaneously characterizing the metabolite profile of Berberis julianae fruits, identifying bioactive alkaloid-enriched fractions, and evaluating their cytotoxicity in neuronal cell models. Methods: Methanolic extracts of B. julianae fruits were profiled by HPLC-ESI-QTOF-MS/MS and fractionated using centrifugal partition chromatography (CPC). The developed FAIA, based on 4-methylumbelliferyl acetate as a fluorogenic substrate, was optimized and validated using berberine as a reference inhibitor. CPC fractions and selected protoberberine alkaloids were screened for AChE-inhibitory activity, while cytotoxicity was assessed in differentiated and undifferentiated SH-SY5Y cells using the resazurin assay. Results: Twenty-five metabolites, including eight isoquinoline alkaloids, were tentatively identified in the fruit extract. The optimized FAIA enabled reliable evaluation of AChE inhibition without the limitations associated with chromogenic assays. Among the CPC fractions, fraction 7 exhibited the strongest inhibitory activity. LC-MS analysis revealed that this fraction was enriched in protoberberine alkaloids, including berberine, palmatine, jatrorrhizine, magnocurarine, and demethyleneberberine. Cytotoxicity studies demonstrated concentration-dependent effects of both the isolated fractions and the individual alkaloids, with differentiated and undifferentiated SH-SY5Y cells exhibiting distinct sensitivity profiles. At 200 µg/mL, cell viability ranged from approximately 20–40% in undifferentiated SH-SY5Y cells and from approximately 25–45% in differentiated SH-SY5Y cells, depending on the CPC fraction. Among the tested protoberberine alkaloids, demethyleneberberine exhibited the lowest cytotoxic effect, maintaining the highest viability of differentiated SH-SY5Y cells, followed by jatrorrhizine and berberine. Conclusions: The proposed FAIA represents a sensitive and practical approach for screening AChE inhibitors in complex plant matrices. Combined with metabolomic profiling and CPC-based bioassay-guided fractionation, it enabled the identification of alkaloid-rich fractions of B. julianae with pronounced anti-AChE activity. These findings support the applicability of the developed workflow for natural-product-based drug discovery targeting neurodegenerative disorders. Full article

Background/Objectives: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition characterised by cognitive impairment, cholinergic deficiency and neuroinflammation. Carvacrol and thymol are two related natural monoterpenes with reported antioxidant, anti-inflammatory, anti-apoptotic and cholinesterase-inhibiting properties. This scoping review aims to map the current evidence regarding the effects of carvacrol and thymol on AD-related pathologies and identify their mechanisms of action. Methods: A systematic literature search was conducted in February 2026 across PubMed, Scopus and Web of Science. This review included original, English-language primary research articles investigating the effects of carvacrol and thymol on AD using in vitro, in vivo, or in silico models. Results: From an initial pool of 87 unique records, 30 primary studies met the inclusion criteria, encompassing direct AD pathology models (e.g., amyloid-beta), AD-associated risk models (e.g., metabolic or hypertensive impairment), and general cognitive impairment models. Both carvacrol and thymol reduced escape latency during spatial learning acquisition training and increased time spent in the target quadrant during probe trials, indicating improvements in both learning and memory retention, although several studies reported non-linear relationships. At the cellular level, carvacrol and thymol modulated distinct redox and inflammatory pathways, including nuclear factor erythroid 2-related factor 2 upregulation and tumour necrosis factor-alpha suppression. Synthetic derivatives and nanocarrier formulations (e.g., liposomes, nanoemulsions) demonstrated enhanced acetylcholinesterase inhibition and biological stability relative to parent monoterpenes. No clinical trials were identified, and formal critical appraisal was not performed. Conclusions: Preclinical evidence indicates that carvacrol and thymol show potential multi-targeted neuroprotective activity across diverse models of cognitive dysfunction. However, clinical translation remains unproven due to heterogeneous experimental designs, pharmacokinetic limitations, a lack of human trials, and unassessed study quality. Full article

Acute myocardial infarction (AMI) is a leading cause of death worldwide, characterised by systemic inflammation and metabolic disorders. Tetrahydropalmatine (THP) and berberine (BBR) are major alkaloids derived from Corydalis yanhusuo and Coptis chinensis, respectively, both of which have been shown to be cardioprotective; however, whether their mechanisms differ remains unclear. In this study, we systematically compared THP and BBR in treating AMI using integrated spatial metabolomics (AFADESI-MSI), untargeted metabolomics, lipidomics, and molecular biology. The results showed that both compounds improved cardiac function, reduced fibrosis, and suppressed inflammation. Multi-omics revealed that although both regulate glycerophospholipid metabolism, their pathway preferences and functional roles diverge: THP primarily affects linoleic acid and acetylcholine metabolism with a greater propensity to restore membrane structural integrity, whereas BBR targets ether phospholipids and sphingolipids with preferential anti-inflammatory lipid modulation. At the enzymatic level, both downregulated CHKα, PEMT, ChAT, and PDHA1. A key difference is that THP uniquely upregulated acetylcholinesterase (AChE) mRNA expression, an effect absent with BBR. Spatial metabolomics directly visualised that both compounds reverse the accumulation of pro-inflammatory lysophosphatidylcholines (LPCs) and restore structural phosphatidylcholines (PCs) in the infarct region, thereby re-establishing regional lipid homeostasis. To our knowledge, this is the first integrated multi-omics comparison to suggest shared and distinct mechanisms of THP and BBR in AMI. Notably, the differential regulation of AChE, as visualised by spatial omics, may serve as a molecular basis for understanding their distinct therapeutic features, although further validation at the protein and enzymatic activity levels is warranted. 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

Background/Objectives: Symmetrical dual-site acetylcholinesterase (AChE) inhibitors offer a compelling strategy to mitigate mutational drug resistance, yet static modeling fails to capture induced-fit dynamics under mutational stress. Methods: Here, a 100,000-compound virtual library was filtered using a machine learning-based QSAR classification pipeline. A strict, empirically calibrated Jaccard applicability domain filter (AD = 0.823) eliminated topological anomalies, yielding a robust cross-validation accuracy (ROC-AUC: 0.80 ± 0.05; independent test MCC: 0.61). Multi-parameter ADMET and shape screening prioritized unique chemotypes to probe the 20 Å enzyme gorge. All-atom explicit-solvent molecular dynamics simulations were coupled with 150 ns enhanced-sampling Metadynamics along two orthogonal collective variables (gorge depth and ligand orientation) to map out the free energy surfaces under mutational stress. Results: Symmetrical probes suffered catastrophic unbinding upon anchor loss. Conversely, the symmetrical core of Lead Compound 1631 demonstrated extraordinary structural resilience. In silico site-directed mutagenesis (W86A and W286A) triggered a thermodynamic locking effect; the W86A mutant forced the complex into a deeper energetic well (ΔG_min = 9.23 ± 1.98 kJ/mol) than the wild-type state (5.26 ± 1.69 kJ/mol). MM/GBSA decomposition confirmed an active electrostatic-solvation compensation mechanism along a “solvation see-saw” diagonal (ΔΔG_total = +1.59 kcal/mol). Finally, Dynamic Cross-Correlation Matrix analysis quantified a mechanical inversion of the CAS-PAS axis into an anti-correlated clamping mode (−0.04) that locked the ligand bridge in place. Conclusions: These results demonstrate that symmetrical dual-site targeting, combined with dynamic thermodynamic locking, provides a resilient framework to overcome mutational resistance in AChE inhibitors. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative condition marked by a gradual decline in cognitive abilities, a reduction in acetylcholine (ACh) levels, and the accumulation of β-amyloid (Aβ) plaques. In a healthy brain, approximately 80% of ACh is broken down by acetylcholinesterase (AChE). Meanwhile, butyrylcholinesterase (BChE) serves a supportive function, gaining significance as AChE activity diminishes during the progression of Alzheimer’s disease. Modern therapeutic approaches focus on creating dual inhibitors of AChE and BChE that also aim to diminish Aβ-amyloidogenesis through interactions with the peripheral anionic site (PAS). This study combined fragment-based molecular design (CReM), AI-assisted retrosynthetic feasibility assessment, and in silico evaluation (docking, molecular dynamics, and ADMET profiling) to identify novel Donepezil derivatives as potential dual AChE/BChE inhibitors. A series of 10,000 derivatives were developed through computational methods and carefully assessed based on stringent drug-likeness, synthetic accessibility, and medicinal chemistry standards. This was succeeded by comprehensive ADMET profiling. Nine candidates were identified with predicted CNS pharmacokinetics, adequate toxicological profiles and reduced cytochrome P450 liabilities. Molecular docking yielded improved predicted binding affinities relative to Donepezil. Several derivatives, particularly D4 and D5, showed dual-site binding poses spanning both the catalytic gorge and the PAS. MD simulations indicated the stability of these poses over 100 ns. These computational results suggest that the proposed derivatives may preserve or improve upon Donepezil’s pharmacokinetic profile while offering potentially balanced AChE/BChE inhibition and anti-amyloidogenic activity, pending experimental validation. Full article

Background: Concurrent use of acetylcholinesterase inhibitors (AChEIs) and medicines with anticholinergic activity is a clinically important medication safety concern in dementia care because these medicines may pharmacologically oppose dementia treatment and increase the risk of avoidable harm. This review systematically synthesised evidence on the prevalence, patterns, predictors and clinical consequences of concurrent use of anticholinergic and anti-dementia drugs (ADDs) in older adults with dementia. Methods: A PRISMA-informed systematic review was conducted employing Ovid MEDLINE, Embase and PsycINFO from January 2010 to April 2026. Observational studies were eligible if they included older adults with dementia and reported concurrent exposure to at least one anticholinergic medicine and an ADD, defined as AChEIs and/or memantine. Study quality was appraised using the Newcastle–Ottawa Scale. Results: Twenty-eight studies were included, spanning community, outpatient memory-clinic, acute hospital, long-term care and population-based settings. Two distinct exposure constructs were identified: (1) temporal co-prescribing and (2) cumulative anticholinergic burden among ADD users. Reported prevalence varied markedly according to the exposure definition and setting. Concurrent use was lowest in studies limited to bladder antimuscarinic overlap, generally around 5–13%,but increased to 20–45% when broader anticholinergic definitions were used. In long-term care and institutional cohorts, concurrent exposure reached 61–67%. Recurring predictors included polypharmacy, fragmented care or multiple prescribers, urinary symptoms, behavioural and psychological symptoms of dementia, Parkinson’s disease and non-geriatric prescribing. One large population-based study reported that high anticholinergic burden was associated with treatment modification of AChEIs (aHR 1.12), delirium (aHR 1.52), and two-year mortality (aHR 1.23). Additional studies reported associations with longer hospital stays or readmission. Conclusions: Concurrent use of anticholinergic medicines and ADDs is a common, clinically important and potentially modifiable medication-safety problem in dementia care. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, cholinergic dysfunction, and amyloid-β (Aβ) aggregation. Tri-Sannibat-Phol (TSB), a classical Thai polyherbal formulation comprising Piper retrofractum fruit, Ocimum tenuiflorum root, and Piper nigrum root, has been traditionally used for its medicinal properties, yet its anti-AD potential has never been scientifically evaluated. Methods: The therapeutic potential of TSB was investigated through in vitro bioassays including antioxidant, acetylcholinesterase (AChE) inhibitory, and anti-Aβ aggregation assays, alongside neuroprotective evaluation in H₂O₂-induced SH-SY5Y neuroblastoma cells. Acute oral toxicity was assessed in male ICR mice in accordance with OECD Guideline 420. Cognitive-enhancing effects were evaluated using the modified Y-maze, Novel Object Recognition, and Morris Water Maze tests in a scopolamine-induced amnesic mouse model. LC-MS/MS analysis was performed for phytochemical characterization and chemical standardization of the formulation. Results: TSB demonstrated significant antioxidant activity, AChE inhibitory activity, and anti-Aβ aggregation effects, with P. nigrum and O. tenuiflorum identified as the primary contributing components. Neuroprotective effects were confirmed in H₂O₂-induced SH-SY5Y cells, where TSB significantly improved cell viability across concentrations of 1–100 µg/mL. Acute oral toxicity assessment revealed an LD₅₀ exceeding 2000 mg/kg, indicating a favorable safety profile. In vivo behavioral studies demonstrated that TSB at medium-to-high doses significantly reversed scopolamine-induced cognitive deficits across all three behavioral tests. LC-MS/MS analysis identified thirteen piperidine alkaloids, with piperine as the dominant constituent at 17.61 ± 0.80% w/w, proposed as the primary bioactive driver and chemical marker for future quality standardization. Conclusions: These findings suggest that TSB exerts multi-targeted anti-AD effects through complementary mechanisms, supporting its potential as a traditional medicine-based therapeutic candidate for further preclinical and clinical investigation. Full article

The Amaryllidaceae family is a rich source of structurally diverse alkaloids with recognized neuroactive and antiparasitic properties. This study provides the first phytochemical and biological characterization of Pyrolirion boliviense and wild Stenomesson miniatum from Bolivia. Alkaloid extracts from bulbs and leaves were analysed by GC–MS and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Trypanosoma cruzi inhibitory activities. Thirty-two Amaryllidaceae alkaloids were identified, with P. boliviense exhibiting greater alkaloid diversity (25 compounds) and S. miniatum a higher total alkaloid content (227.86 vs. 138.92 μg Gal/100 mg DW). P. boliviense bulb extracts showed the strongest cholinesterase inhibition (AChE IC₅₀ = 6.07 ± 0.47 μg·mL⁻¹; BuChE IC₅₀ = 30.93 ± 1.17 μg·mL⁻¹), whereas S. miniatum extracts displayed weaker AChE inhibition and no detectable BuChE activity. In anti-T. cruzi assays, bulb extracts were the most active, with S. miniatum showing an IC₅₀ of 0.90 ± 0.15 μg·mL⁻¹ (SI = 20.12) and selective anti-amastigote activity (IC₅₀ = 1.42 ± 0.66 μg·mL⁻¹; SI = 12.77). These findings identify Bolivian Andean Amaryllidaceae as promising sources of bioactive alkaloids with potential applications for Alzheimer’s disease and Chagas disease drug discovery. 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

Prospero autumnale L. is a Mediterranean medicinal plant traditionally employed for inflammatory and neurological disorders. Nonetheless, its safety profile, toxicity, and application for treating inflammation and pain are yet to be comprehensively established. This investigation aimed to assess the bioactivity and toxicity of extracts derived from its aerial (AgP) and underground (UgP) parts. The phytochemical constituents of various P. autumnale extracts were analyzed using LC-MS/MS, and their phenolic content was quantified. The biological activities were evaluated through in vitro assays—including antioxidant, anti-inflammatory, acetylcholinesterase-inhibitory, and photoprotection assessments—and in vivo experiments, including evaluations of acute oral toxicity, anti-inflammatory, and analgesic effects. UgP extracts demonstrated significant antioxidant activity, with the methanolic extract exhibiting the highest reducing and superoxide scavenging capacities. Dichloromethane and ethyl acetate extracts performed exceptionally well in ABTS and DPPH assays. The aqueous extract from AgP exhibited noteworthy anti-inflammatory and analgesic effects, surpassing diclofenac in vitro and demonstrating efficacy in vivo. It also showed considerable acetylcholinesterase inhibition, while the ethyl acetate extract displayed high photoprotective potential. The acute toxicity was moderate (LD₅₀: 300–400 mg/kg), indicating dose-dependent risks. LC-MS/MS analysis revealed diverse phenolics potentially contributing to both therapeutic and adverse effects. This research enhances the medicinal prospects of P. autumnale, provides new perspectives on plant utilization, and suggests its potential as a natural anti-inflammatory agent. However, due to moderate toxicity and dose-dependent effects, cautious application is advised. These findings underscore the importance of toxicological evaluation alongside bioactivity screening in ethnopharmacology to ensure safety. Full article

The genus Tamarix L. includes several species widely used in traditional medicine for their therapeutic properties. This study aims to evaluate the bioactive potential of Tamarix gallica extracts from Western Algeria using an integrated in vitro and in silico approach. GC–MS analysis with BSTFA derivatization was performed to characterize the chemical profile of the methanolic fraction. In addition, total phenolic, flavonoid, and tannin contents were determined in methanolic extracts of leaves and stems. The biological activities were assessed using antioxidant (DPPH, ABTS, β-carotene, FRAP, O-phenanthroline, and cupric reducing assays), antimicrobial, antidiabetic, and anti-Alzheimer in vitro assays. Molecular docking was conducted to evaluate the inhibitory potential of selected flavonoids against α-amylase, acetylcholinesterase, and butyrylcholinesterase. Results revealed a rich metabolite profile dominated by long-chain aliphatic alcohols (including hentriacontan-12-ol), phytosterols (β-sitosterol), fatty acids, phenolic derivatives, and sugar alcohols. The extracts exhibited strong antioxidant activity (IC₅₀ = 1.34 ± 0.43 and 12.32 ± 0.36 μg·mL⁻¹), significant antimicrobial effects against the tested pathogens, and notable antidiabetic and anticholinesterase activities (IC₅₀ = 78.65 ± 1.43 and 98.37 ± 1.07 μg·mL⁻¹). Molecular docking analysis supported these findings, showing strong binding affinities of quercetin and rhamnetin toward the target enzymes. Overall, T. gallica exhibits promising multifunctional bioactivities with potential pharmaceutical relevance. Full article

Chronic depression is associated with oxidative stress, neuroinflammation, neurotransmitter imbalance, and Alzheimer’s-like changes. Current monoamine oxidase inhibitors have limited cognitive benefits and disease-modifying properties. A new nanotherapeutic, combining chitosan nanoparticles, propargylamino-1-(4-methylthiophenyl) propane (PAMTP), and L-tyrosine (En@PAMTP_Tyr), was developed. En@PAMTP_Tyr nanoparticles were ~140 nm in diameter, with a zeta potential of +27 mV and entrapment efficiencies of 73.45% for PAMTP and 90.85% for L-tyrosine. Drug release was pH-sensitive, favoring acidity. Intraperitoneal administration of En@PAMTP_Tyr reduced anhedonia, despair, cognitive deficits, and neuromuscular weakness, with efficacy matching or exceeding that of selegiline. In treated rats’ hippocampal tissue, En@PAMTP_Tyr increased superoxide dismutase and glutathione, normalized MAO and acetylcholinesterase activities, and corrected CUSD-induced TNF-α and IL-10 changes, showing antioxidant and anti-inflammatory effects. Histological analyses revealed that En@PAMTP_Tyr preserved CA1 pyramidal neurons, reduced β-amyloid levels, restored tau protein, and improved brain-derived neurotrophic factor levels, indicating reduced neurodegeneration. Molecular docking studies showed that PAMTP had high affinity for monoamine oxidase and acetylcholinesterase, supporting its role as an MAO-B inhibitor and cholinergic modulator. These findings suggest that En@PAMTP_Tyr is a promising nanoplatform for targeting MAO-B in depression, addressing mood, cognitive function, oxidative stress, inflammation, and Alzheimer-like pathology in the hippocampus. Full article

Taraxacum mongolicum, a medicinal and edible plant of the Asteraceae family, is widely consumed in East Asia and contains diverse bioactive compounds. This study systematically evaluated the bioactivities of whole-plant extracts and their components and elucidated the underlying anti-inflammatory mechanisms. Among the extracts, the methanol fraction exhibited the strongest antioxidant activity, effective inhibition of nitric oxide (NO) production, and modulation of inflammation-related proteins. In addition, the extracts demonstrated α-glucosidase and acetylcholinesterase (AChE) inhibitory activities, indicating multifunctional bioactive potential. Activity-guided analysis identified luteolin (2) and apigenin (4) as key active compounds with strong NO inhibitory effects. Western blot analysis revealed that both compounds significantly downregulated NO-related protein expression. Mechanistically, luteolin attenuated inflammatory responses by inhibiting NF-κB signaling and modulating the MAPK pathway, whereas apigenin primarily exerted its effects through NF-κB suppression. Both compounds also promoted M2 macrophage marker expression, suggesting a role in immune regulation. Molecular docking analysis further confirmed stable binding interactions of luteolin and apigenin with iNOS and COX-2. Overall, these findings demonstrate that T. mongolicum possesses antioxidant, enzyme-inhibitory, and anti-inflammatory activities and supports its further investigation as a multifunctional bioactive resource. 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