Search Results (91)

Cholinergic neuron impairment is a significant cause of cognitive decline in Alzheimer’s disease (AD), making acetylcholinesterase (AChE) a key therapeutic target. AChE inhibitors are principal drugs prescribed to alleviate symptoms in AD patients, while up to 50% of these individuals also suffer from depression, frequently treated with selective serotonin reuptake inhibitors (SSRIs). Due to the multisymptomatic nature of AD, there is a growing interest in developing multitargeted ligands that simultaneously enhance cholinergic and serotonergic tone. This study presents the synthesis of novel ligands based on functionalized piperidines, evaluated through radioligand binding assays at the serotonin transporter (SERT) and AChE and butyrylcholinesterase (BuChE) inhibition. The pharmacological results showed that some compounds exhibited moderate inhibitory activity against AChE, with one compound 19 standing out as the most potent, also displaying a moderate BuChE inhibitory activity, while showing low affinity for SERT. On the other hand, compound 21 displayed an interesting polypharmacological profile, with good and selective activity against BuChE and SERT. The results underscore the difficulty of designing promiscuous ligands for these targets and suggest that future structural modifications could optimize their therapeutic potential in AD. Full article

In Argentina and globally, pistachio (Pistacia vera) production has significantly grown, driven by its high nutritional value and food industry demand. Its harvesting and processing generate about 40% of pistachio waste (PW), including leaves, twigs, seed coats, green, and empty kernels. Underutilized PW has led to environmental problems, including soil and water contamination by landfill accumulation. However, it could be a potential source of undiscovered bioactive compounds. This study aimed to characterize the chemical profile and to evaluate the bioactive properties of PW. The dried pistachio waste (dPW) was used to prepare the pistachio waste decoction (PWD) (10% w/v). The total phenolic content (TPC) and flavonoid content (FC) were quantified, and the chemical profile was analyzed using UPLC-DAD-ESI-MS/MS. Nematicidal activity against Meloidogyne incognita (J2), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, antioxidant capacity (ABTS, DPPH, FRAP), and phytotoxicity on Allium cepa, Lactuca sativa, and Raphanus sativus were evaluated. The UPLC-DAD-ESI-MS/MS analysis identified 26 compounds, including phenolics, flavonoids, and unsaturated fatty acids. The main compounds were gallic acid, anacardic acid, and quercetin derivatives. The TPC and FC were 212.65 mg GAE/g dPW and 0.022 mg QE/g dPW, respectively, displaying strong antioxidant activity across the assays DPPH, ABTS, and FRAP. PWD exhibited nematicidal activity against M. incognita (J2) (LC₅₀ = 0.12% at 24 h). Alterations in the cuticle were observed, including structural disorganization and detachment from internal tissues. Additionally, a remarkable cholinesterase inhibitory effect was detected at 2.0% PWD (42.65% for AChE and 58.90% for BuChE). PWD showed low phytotoxic effects across the tested species, and the germination percentage (GP) and the mean germination time (MGT) were not significantly affected (GP > 79%). These findings highlight the potential of PW as a sustainable alternative for M. incognita control, the remarkable nematicidal, anticholinesterase, and antioxidant properties, and the low phytotoxicity, supporting its use in sustainable agricultural practices. Full article

A series of bisuracils, in which uracil and 3,6-dimethyluracil moieties were bridged with a polymethylene spacer, and the uracil moiety contained a pentamethylene radical with ionic and non-ionic aminobenzyl groups, were synthesised. These bisuracils have been identified as cholinesterase inhibitors with exceptional selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). These bisuracils, which have been identified as highly effective AChE inhibitors, demonstrated activity at nano- and sub-nanomolar concentrations, with exceptional selectivity for AChE over BuChE. In kinetic studies of lead bisuracils 2b and 3c, both compounds exhibited mixed-type inhibition against AChE and BuChE. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 2b and 3c with the binding sites of their target. Bisuracil 2b showed significant potential for protection of AChE from irreversible inhibition by paraoxon; the most effective dose of 0.01 mg/kg was shown to reduce mortality in paraoxon-poisoned mice. Bisuracil 3c effectively inhibited brain AChE activity, reversing scopolamine-induced amnesia in mice at a dose of 5 mg/kg, which indicates its potential for cognitive enhancement. These findings position ionic bisuracils as promising prophylactics against organophosphate poisoning and non-ionic bisuracils as viable candidates for Alzheimer’s disease therapeutics. Full article

Marine macroalgae are excellent sources of bioactive compounds recognized by their pharmaceutical and biomedical potential. A subcritical water extraction (SWE) was applied to the macroalga Codium tomentosum, and the extract was used to prepare phytosomes. A Box–Behnken design was applied to optimize the entrapment efficiency. These phytosomes were further modified with DSPE-PEG (2000)-maleimide and apolipoprotein E and characterized by dynamic light scattering, UV spectrophotometry, octanol/water partition coefficient, differential scanning calorimetry, and Fourier transform infrared spectroscopy. As proof of concept, prototypes of functional food tailored to the elderly were produced. Yogurts were fortified with seaweed extract or phytosomes, and physicochemical properties and proximal composition (pH, acidity, syneresis, moisture, peroxides, proteins, total lipids, sugar content, ash, and mineral composition) were analyzed. The antioxidant and the inhibition capacity of two brain enzymes, cholinesterases (AChE and BuChE), involved in the pathogenesis of Alzheimer’s disease, were also evaluated in the final prototypes. Despite their unappealing sensory characteristics, the results are promising for integrating marine extracts with potential neuroprotective effects into functional foods. Full article

Hieronymiella peruviana, a recently described endemic species from southern Peru, belongs to the Amaryllidaceae family and is known for its diversity of alkaloids. Amaryllidoideae have been studied for their diverse biological activities, particularly for their properties in treating neurodegenerative diseases. This work examines the alkaloidal profile using GC-MS and UPLC-MS/MS of alkaloid-enriched extracts obtained from the leaves and bulbs of H. peruviana and their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. In addition, the phenolic and flavonoid content in the methanolic extract from bulbs was quantified and the antioxidant capacity was evaluated. Moreover, the seed germination was investigated under four temperature conditions (15, 20, 25, and 30 °C). Twenty-two alkaloids, most of them of the homolycorine- and galanthamine-type, including galanthamine, were identified in the alkaloid extracts by means of GC-MS and UPLC-MS/MS analysis. Lycorine and 8-O-Demethylhomolycorine were the most abundant alkaloids in the bulbs and leaves, respectively. The leaves and bulbs alkaloid extracts demonstrated strong AChE inhibition (IC₅₀ = 5.20–8.60 µg/mL) and moderate BuChE inhibition (IC₅₀ = 90.20–122.76 µg/mL). The bulbs’ methanolic extract exhibited mild antioxidant activity, showing 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) values of 16.36% at 500 μg/mL and 58.31 mg Trolox equivalents (TE)/g, respectively. Seed germination was most effective at 20 °C and 25 °C. Finally, 60 days after germination, the survival rate of H. peruviana seedlings was 48.33%. These findings establish H. peruviana as a promising source of bioactive alkaloids with potential pharmacological and therapeutic applications, as well as providing critical insights for its propagation and conservation. Full article

Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, ¹H NMR, and ¹³C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC₅₀ values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and −13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer’s disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors. Full article

Combining the pharmacological properties of the 1,2,3-triazole and dihydropyrimidinone classes of compounds, two small families of mono- and di(1,2,3-triazole)-dihydropyrimidinone hybrids, A and B, were previously synthesized. The main objective of this work was to investigate the potential anti-Alzheimer effects of these hybrids. The inhibitory activities of cholinesterases (AChE and BuChE), antioxidant activity, and the inhibitory mechanism through in silico (molecular docking) and in solution (STD-NMR) experiments were evaluated. The 1,2,3-triazole-dihydropyrimidinone hybrids (A and B) showed moderate in vitro inhibitory activity on eqBuChE (IC₅₀ values between 1 and 58.4 μM). The best inhibitor was the hybrid B4, featuring two 1,2,3-triazole cores, which exhibited stronger inhibition than galantamine, with an IC₅₀ of 1 ± 0.1 μM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC₅₀ of 12 ± 2 µM, similar to that of galantamine. Molecular docking and STD-NMR experiments revealed the key binding interactions of these promising inhibitors with BuChE. Hybrids A and B did not display Artemia salina toxicity below 100 μM. Full article

Background: Alzheimer’s disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer’s disease. Co-targeting GSK3β and BChE in Alzheimer’s disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer’s disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Results: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of −9.6 and −12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. Conclusion: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer’s disease, capable of simultaneously inhibiting both GSK-3β and BuChE. Full article

The fruit juice industry generates a significant amount of waste, with a strong impact on the environment and the economy. Therefore, researchers have been focusing on the characterization of resources considered as food waste. This work provides information about the lipophilic and polar metabolites of pear pomace flours (PPFs) as a tool that can shed more light on the bioactive potential of this residue. Using UPLC-PDA, UPLC-FLR, and GC-MS, the study identified and quantified PPF’s polar and non-polar metabolites. Essential, conditional, and non-essential amino acids were found, with asparagine being the most abundant. Isoprenoids, including lutein, zeaxanthin, and carotene isomers, ranged from 10.8 to 22.9 mg/100 g dw. Total flavonoids and phenolic compounds were 520.5–636.4 mg/100 g dw and 536.9–660.1 mg/100 g dw, respectively. Tocotrienols and tocopherols were identified, with concentrations of 173.1–347.0 mg/100 g dw and 468.7–913.4 mg/100 g dw. Fatty acids were the major non-polar compounds. All fractions significantly reduced matrix metalloproteinase-9 (MMP-9) activity. Although PPF had lower antioxidant potential (3–6 mmol Trolox/100 g dw), it inhibited AChE and BuChE by 23–30% compared to physostigmine salicylate. These findings suggest that pear pomace waste can be repurposed into functional products with valuable bioactive properties by re-introducing it in the food chain. Full article

Five putrescine and spermidine derivatives (1–5) together with five rotenoids (6–10) were isolated from a methanolic extract of the flowers of A. fruticosa that displayed promising inhibition of 76.0 ± 1.9% for AChE and 90.0 ± 4.0% for BuChE at a concentration of 1 mg/mL. Although the anticholinesterase activities of the isolated compounds did not reach that of galantamine, molecular docking revealed that all-trans-tri-p-coumaroylspermidine and trans-trans-cis-tri-p-coumaroylspermidine showed binding poses mimicking the known inhibitor galantamine and thus could serve as model molecules in future searches for new AChE and BuChE inhibitors. Full article

Narcissus L. is a renowned plant genus with a notable center of diversity and is primarily located in the Mediterranean region. These plants are widely recognized for their ornamental value, owing to the beauty of their flowers; nonetheless, they also hold pharmacological importance. In Europe, pharmaceutical companies usually use the bulbs of Narcissus pseudonarcissus cv. Carlton to extract galanthamine, which is one of the few medications approved by the FDA for the palliative treatment of mild-to-moderate symptoms of Alzheimer’s disease. The purpose of this study was to evaluate the potential of these plants in Alzheimer’s disease. The alkaloid extract from the leaves of different species of Narcissus was obtained by an acid-base extraction work-up -procedure. The biological potential of the samples was carried out by evaluating their ability to inhibit the enzymes acetyl- and butyrylcholinesterase (AChE and BuChE, respectively). The species N. jacetanus exhibited the best inhibition values against AChE, with IC₅₀ values of 0.75 ± 0.03 µg·mL⁻¹, while N. jonquilla was the most active against BuChE, with IC₅₀ values of 11.72 ± 1.15 µg·mL⁻¹. Full article

Alzheimer’s disease is associated with protein aggregation, oxidative stress, and the role of acetylcholinesterase in the pathology of the disease. Previous investigations have demonstrated that geniposide and harpagoside protect the brain neurons, and cerium nanoparticles (CeO₂ NPs) have potent redox and antioxidant properties. Thus, the effect of nanoparticles of Ce NPs and geniposide and harpagoside (GH/CeO₂ NPs) on ameliorating AD pathogenesis was established on AlCl₃-induced AD in mice and an aggregation proteins test in vitro. Findings of spectroscopy analysis have revealed that GH/CeO₂ NPs are highly stable, nano-size, spherical in shape, amorphous nature, and a total encapsulation of GH in cerium. Treatments with CeO₂ NPs, GH/CeO₂ NPs, and donepezil used as positive control inhibit fibril formation and protein aggregation, protect structural modifications in the BSA-ribose system, have the ability to counteract Tau protein aggregation and amyloid-β1–42 aggregation under fibrillation condition, and are able to inhibit AChE and BuChE. While the GH/CeO₂ NPs, treatment in AD induced by AlCl₃ inhibited amyloid-β1–42, substantially enhanced the memory, the cognition coordination of movement in part AD pathogenesis may be alleviated through reducing amyloidogenic pathway and AChE and BuChE activities. The findings of this work provide important comprehension of the chemoprotective activities of iridoids combined with nanoparticles. This could be useful in the development of new therapeutic methods for the treatment of neurodegenerative diseases. Full article

Benzimidazole-based pyrrole/piperidine analogs (1–26) were synthesized and then screened for their acetylcholinesterase and butyrylcholinesterase activities. All the analogs showed good to moderate cholinesterase activities. Synthesized compounds (1–13) were screened in cholinesterase enzyme inhibition assays and showed AChE activities in the range of IC₅₀ = 19.44 ± 0.60 µM to 36.05 ± 0.4 µM against allanzanthane (IC₅₀ = 16.11 ± 0.33 µM) and galantamine (IC₅₀ = 19.34 ± 0.62 µM) and varied BuChE inhibitory activities, with IC₅₀ values in the range of 21.57 ± 0.61 µM to 39.55 ± 0.03 µM as compared with standard allanzanthane (IC₅₀ = 18.14 ± 0.05 µM) and galantamine (IC₅₀ = 21.45 ± 0.21 µM). Similarly, synthesized compounds (14–26) were also subjected to tests to determine their in vitro AChE inhibitory activities, and the results obtained corroborated that all the compounds showed varied activities in the range of IC₅₀ = 22.07 ± 0.13 to 42.01 ± 0.02 µM as compared to allanzanthane (IC₅₀ = 20.01 ± 0.12 µM) and galantamine (IC₅₀ = 18.05 ± 0.31 µM) and varied BuChE inhibitory activities, with IC₅₀ values in the range of 26.32 ± 0.13 to 47.03 ± 0.15 µM as compared to standard allanzanthane (IC₅₀ = 18.14 ± 0.05 µM) and galantamine (IC₅₀ = 21.45 ± 0.21 µM). Binding interactions of the most potent analogs were confirmed through molecular docking studies. The active analogs 2, 4, 10 and 13 established numerous interactions with the active sites of targeted enzymes, with docking scores of −10.50, −9.3, −7.73 and −7.8 for AChE and −8.97, −8.2, −8.20 and −7.6 for BuChE, respectively. Full article

Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as a treatment in combination with artesunate. Although MQ has clear anti-Plasmodium falciparum properties, it can induce neurotoxicity and undesired neuropsychiatric side effects in humans. Hence, this study aimed to characterize the neurotoxicity of MQ using human neuroblastoma SH-SY5Y cells. The effects of MQ on neuronal toxicity and cell viability were investigated over a concentration range of 1–100 µM using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The influence of MQ on cellular bioenergetics was examined by measuring cellular ATP levels and from the induction of reactive oxygen species (ROS). An in silico approach was used to assess the potential neurotoxicity of MQ mediated via binding to the active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and then experimentally validated via in vitro enzymatic assays. MQ was cytotoxic to neuronal cells in a concentration and exposure duration dependent manner and induced a significant reduction in viability at concentrations of ≥25 µM after a 24 h exposure. MQ adversely impacted cellular bioenergetics and significantly depleted ATP production at concentrations of ≥1 µM after 24 h. MQ-induced cellular ROS production, which was correlated with the induction of apoptosis, as revealed by flow cytometry. In silico studies suggested that MQ was a dual cholinesterase inhibitor and one with remarkably potent binding to BuChE. Modelling data were supported by in vitro studies which showed that MQ inhibited both human AChE and BuChE enzymes. In summary, MQ is an antimalarial drug that may induce neurotoxicity by impacting cellular bioenergetics and perturbing the activity of cholinesterases at exposure concentrations relevant to human dosage. Full article