Search Results (555)

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder with a pressing need for novel therapeutics. However, current medications only offer symptomatic relief, without tackling the underlying pathology. To explore the bioactive potential of marine-derived fungi, this study focused on Aspergillus terreus C23-3, a strain isolated from the coral Pavona cactus in Xuwen County, China, which showed a richer metabolite fingerprint among the three deposited A. terreus strains. AntiSMASH analysis based on complete genome sequencing predicted 68 biosynthetic gene clusters (BGCs) with 7 BGCs synthesizing compounds reported to have anti-AD potential, including benzodiazepines, benzaldehydes, butenolides, and lovastatin. Liquid chromatography coupled with mass spectrometry (LC-MS)-based combinational metabolomic annotation verified most of the compounds predicted by BGCs with the acetylcholinesterase (AChE) inhibitor territrem B characterized from its fermentation extract. Subsequently, molecular docking showed that these compounds, especially aspulvione B1, possessed strong interactions with AD-related targets including AChE, cyclin-dependent kinase 5-p25 complex (CDK5/p25), glycogen synthase kinase-3β (GSK-3β), and monoamine oxidase-B (MAO-B). In conclusion, the genomic–metabolomic analyses and molecular docking indicated that C23-3 is a high-value source strain for anti-AD natural compounds. Full article

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

Alzheimer’s disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure–activity relationships, and their interactions with the molecular targets at the molecular level. Full article

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The compounds were tested for AChE and BChE inhibition. They showed greater potency and selectivity toward BChE. Results: The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also displayed significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolinium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. Conclusions: These findings highlight the potential of new charged triazolinium salts as peripherally selective cholinesterase inhibitors with additional anti-inflammatory potential. Full article

The current study investigates the chemical profiling, antioxidant activities, and enzyme inhibitory and cytotoxic potential of the water and methanolic extracts of different parts (flower, leaf, and bulb) of Muscari armeniacum. Chemical profiling was performed using UHPLC-MS/MS. At the same time, different in vitro assays were employed to support the results for antioxidant potential, such as DPPH, ABTS, FRAP, CUPRAC, metal chelation, and PBD, along with the measurement of total phenolic and flavonoid contents. Enzyme inhibition was investigated for cholinesterase (AChE and BChE), α-amylase, α-glucosidase, and tyrosinase enzymes. Additionally, the relative expression of NRF2, HMOX1, and YGS was evaluated by qPCR. LC-MS/MS analysis indicated the presence of some significant compounds, including apigenin, muscaroside, hyacinthacine A, B, and C, and luteolin. According to the results, the highest TPC and TFC were obtained with both extracts of the leaves, followed by the water extract (flower) and methanolic extract of the bulb. In contrast, the methanolic extract from the bulb exhibited the highest antioxidant potential using DPPH, ABTS, CUPRAC, and FRAP, followed by the extracts of leaves. In contrast, the leaf extracts had the highest values for the PBD assay and maximum chelation ability compared to other tested extracts. According to the enzyme inhibition studies, the methanolic extract from the bulb appeared to be the most potent inhibitor for all the tested enzymes, with the highest values obtained for AChE (1.96 ± 0.05), BChE (2.19 ± 0.33), α-amylase (0.56 ± 0.02), α-glucosidase (2.32 ± 0.01), and tyrosinase (57.19 ± 0.87). Interestingly, the water extract from the bulb did not inhibit most of the tested enzymes. The relative expression of NRF2 based on qPCR analysis was considerably greater in the flower methanol extract compared to the other extracts (p < 0.05). The relative expression of HMOX1 was stable in all the extracts, whereas YGS expression remained stable in all the treatments and had no statistical differences. The current results indicate that the components of M. armeniacum (leaves, flowers, and bulb) may be a useful source of natural bioactive compounds that are effective against oxidative stress-related conditions, including hyperglycemia, skin disorders, and neurodegenerative diseases. Complementary in silico approaches, including molecular docking, dynamics simulations, and transcription factor (TF) network analysis for NFE2L2, supported the experimental findings and suggested possible multi-target interactions for the selected compounds. Full article

Toxicological studies of pesticides in animal models provide critical insights into their mechanisms of action, while adsorption strategies offer potential solutions for decontaminating polluted waters. We evaluated toxicity induced by tetraethyl pyrophosphate (TEPP), an organophosphate pesticide and AChE inhibitor, on zebrafish (Danio rerio) development and behavior, alongside the efficacy of wine cork granules as a natural adsorbent. TEPP exposure reduced embryo viability following an inverted U-shaped dose–response curve, suggesting non-monotonic neurodevelopmental effects, but did not alter developmental timing or morphology in survivors. In juveniles, TEPP increased preference for dark environments (33% vs. controls) and enhanced swimming endurance approximately 3-fold, indicating disrupted phototaxis and stress responses. Most strikingly, water treated with cork granules retained toxicity, increasing mortality, delaying embryogenesis, and altering behavior. This directly contradicts in vitro adsorption studies that suggested cork’s efficacy. These results demonstrate the high sensitivity of zebrafish to TEPP at nanomolar concentrations, which contrasts with in vitro models that require doses approximately 1000 times higher. Our findings not only highlight TEPP’s ecological risks but also reveal unexpected limitations of cork granules for environmental remediation, urging caution in their application. Full article

Background/Objectives: The need for dual-targeted enzyme inhibitors is critical in addressing complex diseases like Alzheimer’s and glaucoma. Imidazothiadiazole and chalcone moieties are known for diverse bioactivities. This study aimed to develop novel imidazothiadiazole–chalcone hybrids as potential inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoforms (hCAs), specifically hCA I and hCA II. Methods: Four hybrid molecules (8a–8d) were synthesized and structurally confirmed via ¹H NMR, ¹³C NMR, FT-IR, MS, and elemental analysis techniques. Their enzyme inhibitory activities were assessed using Ellman’s and Verpoorte’s methods. Molecular docking and 100 ns molecular dynamics (MD) simulations were conducted to examine binding interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted using the pkCSM platform. Results: All compounds showed strong enzyme inhibition: AChE (K_i: 3.86–11.35 nM), BChE (K_i: 1.01–1.78 nM), hCA I (K_i: 45.13–81.24 nM), and hCA II (K_i: 36.08–52.45 nM). Docking analyses confirmed favorable binding, particularly with active-site residues. MD simulations demonstrated stable interactions throughout 100 ns. Compound 8a exhibited the highest cholinesterase inhibition, while compounds 8d and 8c were the most potent against hCA I and hCA II, respectively. The ADMET results showed high absorption and acceptable safety, with mild mutagenicity or cardiotoxicity concerns in select compounds. Conclusions: These findings suggest that imidazothiadiazole–chalcone hybrids are promising multi-target enzyme inhibitors. Their potent activity, structural stability, and pharmacokinetic potential support their further development for therapeutic use in neurodegenerative and ocular diseases. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by progressive neuronal dysfunction and loss and represent a significant global health challenge. Oxidative stress, neuroinflammation, and neurotransmitter dysregulation, particularly affecting acetylcholine (ACh) and monoamines, are key hallmarks of these conditions. The current therapeutic strategies targeting cholinergic and monoaminergic systems have some limitations, highlighting the need for novel approaches. Metallodrugs, especially ruthenium and platinum complexes, are gaining attention for their therapeutic use. Among metal complexes, gold(I) and silver(I) N-heterocyclic carbene (NHC) complexes exhibit several biological activities, but their application in NDDs, particularly as monoamine oxidase (MAO) inhibitors, remains largely unexplored. To advance the understanding of this field, we designed, synthesized, and evaluated the biological activity of a new series of Au(I) and Ag(I) complexes stabilized by NHC ligands and bearing a carboxylate salt of tert-butyloxycarbonyl (Boc)-N-protected proline as an anionic ligand. Through in silico and in vitro studies, we assessed their potential as acetylcholinesterase (AChE) and MAO inhibitors, as well as their antioxidant and anti-inflammatory properties, aiming to contribute to the development of potential novel therapeutic agents for NDD management. Full article

In this study, we analyzed the essential oils (EOs) extracted by steam distillation from the leaves and flowers of Parthenium hysterophorus L., grown in three different locations in southern Ecuador: Espíndola (ESP), Loja (LOJ) and Quilanga (QUI). Approximately 97.45%, 98.27% and 95.99% of the oil constituents were identified using gas chromatography–mass spectrometry (GC-MS) and gas chromatography–flame ionization detection (GC-FID). Sesquiterpene hydrocarbons were predominant in the EOs. The most representative constituents of the sample from ESP were germacrene D (35.08%), myrcene (11.32%), (E)-β-ocimene (10.21%), (E)-caryophyllene (7.90%), germacra-4(15),5,10(14)-trien-1-α-ol (5.18%) and (E, E)-α-farnesene (4.99%), with an AChE IC₅₀ of 14.78 and with 16.38 and 93.16 µg/mL from ABTS and DPPH, respectively. The EOs from LOJ were characterized by the abundant presence of germacrene D (28.30%), myrcene (13.95%), (E)-β-ocimene (10.51%) and isolongifolan-7-α-ol (8.26%), with an AChE IC₅₀ of 16.65 and with 36.18 and 158.43 µg/mL from ABTS and DPPH, respectively. Finally, the EOs from QUI contained germacrene D (32.20%), myrcene (13.36%), (E)-β-ocimene (8.54%), (E, E)-α-farnesene (6.77%), germacra-4(15),5,10(14)-trien-1-α-ol (5.69%) and (E)-caryophyllene (5.37%), with an AChE IC₅₀ of 10.69 and with 14.50 and 92.98 µg/mL from ABTS and DPPH, respectively. This study identifies chemotypic variation in P. hysterophorus collected from different locations and, for the first time, the AChE inhibitor was evaluated. These findings provide a scientific basis for the clinical application of P. hysterophorus EOs in the future treatment of Alzheimer’s disease. Full article

(−)-Patagonic acid (1) is a clerodane diterpene isolated from several plants from the Alismataceae, Asteraceae, Euphorbiaceae, Fabaceae, Lamiaceae, Salicaceae, Sapindaceae, and Velloziaceae families, and its biological potential as an inhibitor of butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) and as an anti-inflammatory compound has been described. Furthermore, the enantiomer (+)-1 is also described in Fabaceae and Verbenaceae. A lack of formal studies about the absolute configuration (AC) determination of 1 is emphasized. Thus, the present manuscript describes the AC determination of patagonic acid (1). The chemical correlation of (−)-1 from (−)-hardwickiic acid (2) was achieved by a simplistic oxidative process. The specific rotation value and electronic circular dichroism (ECD) analysis allowed for the AC determination of (−)-1 as (5R,8R,9S,10R)-(−)-patagonic acid. ECD revealed a positive exciton chirality (EC) phenomenon in both (−)-1 and (−)-2, which is directly associated with their configuration and conformational preferences, which were assessed by DFT calculations at the B3LYP/DGDZVP level of theory. Since the NMR data of (+)-1 are fully coincident with those from its enantiomer studied herein, the chirality of (5S,8S,9R,10S)-(+)-patagonic acid could also be determined. These experimental conclusions deeply complement the literature related to clerodane compounds biosynthesized in several families of plants of scientific interest. Full article

Sitophilus zeamais, a major pest of stored grains, causes significant post-harvest losses and challenges effective control. While synthetic insecticides pose risks of resistance and toxicity, essential oils (EOs) offer a safer alternative. However, the insecticidal potential of their individual volatile constituents (VCs) remains largely unexplored. This study evaluated the insecticidal activity of 51 EO-derived volatile compounds (VCs) against S. zeamais, identifying the most toxic ones, optimizing 15 synergistic mixtures, and assessing their effects on key insect enzymes. A structure–activity relationship (SAR) analysis determined functional groups associated with insecticidal activity, while a cluster analysis pre-selected 29 ternary mixtures, later refined using response surface methodology (RSM). Additionally, enzymatic assays explored their impact on detoxification and nervous system enzymes, providing insights into potential mechanisms of action. Among the 51 VCs tested, 37 exhibited significant toxicity, with 11 acting as fumigants and 13 displaying contact toxicity. Monocyclic monoterpenoids with ketone or alcohol functional groups and exocyclic unsaturation demonstrated the highest insecticidal activity via both exposure routes. Notably, pulegone enantiomers were particularly effective (LC₅₀ < 0.1 mg/L, LD₅₀ < 7.5 µg/adult). Among the optimized mixtures, 10 displayed strong insecticidal effects, 8 were active through both routes, and 5 exhibited synergistic fumigant interactions. The most effective formulations were M2 (R-pulegone + S-pulegone + S-carvone, LC₅₀ 0.48 mg/L) and M20 (isopulegone + δ-3-carene, LC₅₀ 2.06 mg/L), showing the strongest fumigant and synergistic effects, respectively. Enzymatic assays revealed that while some compounds mildly inhibited GST and CAT, others, such as δ-3-carene (IC₅₀ 0.19 mg/L), significantly inhibited AChE. Five mixtures exhibited synergistic neurotoxicity, with M20 (IC₅₀ 0.61 mg/L) and M12 (IC₅₀ 0.81 mg/L) emerging as the most potent AChE inhibitors. These findings highlight the potential of plant-derived volatile compounds as bioinsecticides, leveraging synergistic interactions to enhance efficacy, disrupt enzymatic pathways, and mitigate resistance. Full article

A part of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is caused by mutant CHRNA4. The pathomechanisms underlying motor seizures followingly brief/sudden awakening (paroxysmal arousal) in ADSHE seizures remain to be clarified. This study determined extracellular levels of ACh and L-glutamate in the pedunculopontine nucleus (PPN) and its projection regions, including the thalamus and basal ganglia, during wakefulness, slow-wave sleep (SWS) and paroxysmal arousal of transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG), corresponding to human S284L-mutant CHRNA4, using microdialysis. The expression of connexin43 and pannexin1 in the plasma membrane of the PPN was determined using capillary immunoblotting. The expressions of connexin43 and pannexin1 in the PPN plasma membrane of S286L-TG were larger than the wild type. The extracellular L-glutamate levels in the PPN and projection regions of S286L-TG consistently increased during both wakefulness and SWS compared to the wild type. The extracellular levels of ACh and L-glutamate in the PPN and projection regions decreased accompaning SWS in the wild type. In S286L-TG, this decreasing extracellular ACh level was observed, whereas decreasing L-glutamate level was impaired. Both extracellular levels of ACh and L-glutamate in the PPN and projection regions drastically increased during paroxysmal arousal. Hemichannel inhibitors suppressed the increasing releases of ACh and L-glutamate induced by paroxysmal arousal but decreased and did not affect extracellular levels of L-glutamate and ACh during wakefulness and SWS, respectively. In particular, under hemichannels inhibition, decreasing L-glutamate release accompanying SWS was observed in S286L-TG. This study elucidated that enhanced hemichannels are predominantly involved in the dysfunction of glutamatergic transmission compared to AChergic transmission during the interictal stage in S286L-TG, whereas the hyperactivation of hemichannels contributes to the generation of paroxysmal arousal. Therefore, the hyperactivated excitatory tripartite synaptic transmission associated with hemichannels in the PPN and projection regions plays important roles in epileptogenesis/ictogenesis in S286L-TG. Full article

This manuscript reports the synthesis and characterization of 19 novel heterostilbene carbamates, designed as selective butyrylcholinesterase (BChE) inhibitors with potential applications in the treatment of neurodegenerative disorders, particularly Alzheimer’s disease. The compounds were synthesized from resveratrol analogs, and their structures were confirmed by NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction for selected derivatives (compounds 1 and 4). In vitro assays demonstrated high selectivity toward BChE over acetylcholinesterase (AChE), with compound 16 exhibiting exceptional inhibitory activity (IC₅₀ = 26.5 nM). Furthermore, compound 16 showed moderate anti-inflammatory effects by inhibiting LPS-stimulated TNF-α production in peripheral blood mononuclear cells. In silico ADME(T) profiling revealed favorable pharmacokinetic properties and low mutagenic potential for the majority of compounds. Molecular docking and molecular dynamics simulations confirmed stable binding interactions within the BChE active site. These results highlight heterostilbene carbamates as promising lead structures for developing novel therapeutic agents targeting neurodegenerative diseases. Full article

Schistosomiasis is a parasitic disease caused by helminth parasites of the genus Schistosoma, affecting >200 million people worldwide. Current schistosomiasis treatment relies on a single drug, praziquantel, highlighting the urgent need for new therapies. We have identified a non-neuronal tegumental acetylcholinesterase from Schistosoma mansoni (SmTAChE) as a rational and molecularly defined drug target. Molecular modeling reveals significant structural differences between SmTAChE and human AChE, suggesting the potential for identifying parasite-specific inhibitors. Here, we screened recombinant SmTAChE (rSmTAChE) against two chemical libraries: the Broad Institute Drug Repurposing Hub (5440 compounds) and the Diversity-Oriented Synthesis (DOS)-A library (3840 compounds). High-throughput screening identified 116 hits from the Repurposing Hub (2.13% hit rate) and 44 from the DOS-A (1.14% hit rate) library that inhibited rSmTAChE ≥60% at 20 µM. Dose–response assays using both rSmTAChE and recombinant human AChE (rHsAChE) revealed 19 Repurposing Hub compounds (IC₅₀: 0.4–24 µM) and four DOS-A scaffolds (IC₅₀: 13–29 µM), with higher selectivity for rSmTAChE. Selective inhibitors such as cepharanthine, primaquine, mesalazine, and embelin emerged as promising candidates for further evaluation in schistosomiasis treatment. These 23 newly identified selective hits provide a foundation for the further development of novel anti-schistosome therapies. Full article

Myasthenia gravis is an antibody-mediated autoimmune condition characterized by defects in cholinergic transmission at the neuromuscular junction. In AchR antibody-positive patients, complement activation plays a prominent role in the disease process, which appears to be mediated by the activation of the membrane attack complex. Since IgG4 is not a good complement activator, the role of complement in MuSK antibody-positive myasthenia gravis patients is negligible. Experimental animal models of myasthenia gravis have shown promise with the antagonism of different elements of the complement cascade, with positive clinical outcomes. This has led to the development of the first C5 inhibitors approved for myasthenia gravis with AchR antibodies: eculizumab, ravulizumab, and zilucoplan. Other clinical trials are currently in progress, investigating the potential therapeutic role of other targets, including the Factor B inhibition or hepatic synthesis of the C5 protein. Other proposed potential targets that have not yet been clinically tested are also discussed in this review article. Full article