Search Results (2,146)

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

Eminium rauwolffii (Blume) Schott var. rauwolffii is a member of the Araceae a large and mainly tropical family distributed worldwide. The Eminium species are utilized for various purposes including therapeutic uses in traditional medicine and as food. To analyze the antioxidant properties of water extract of E. rauwolffii (WEER) and ethanol extract of E. rauwolffii (EEER), 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS^•+) radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH^.) free radical scavenging, Fe³⁺-2,4,6-tris(2-pyridyl)-S-triazine (TPTZ) and Cu²⁺ reducing assays were studied. Antioxidant activities and reducing properties of both extracts were compared to standard antioxidants: BHT, BHA, α-Tocopherol, and Trolox. The IC₅₀ values of EEER for radical scavenging were higher than those of standard antioxidants (25.35 ± 1.42 μg/mL for ABTS^•+ and 106.80 ± 1.88 μg/mL for DPPH^•). The total phenolic and flavonoid quantities in WEER and EEER were measured in the range of 189.78 ± 0.01 to 298.54 ± 0.01 mg GAE/g and 89.37 ± 0.01 to 178.95 ± 0.01 mg QE/g, respectively. The IC₅₀ values for EEER and WEER against α-glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carbonic anhydrase I and II (hCA I and II) enzymes were 10.79 ± 5.61 to 13.18 ± 5.77, 36.14 ± 4.61 to 62.63 ± 1.67, 69.37 ± 7.36 to 37.48 ± 0.27, 81.30 ± 5.95 to 62.35 ± 8.03, and 29.34 ± 1.38 to 115.90 ± 3.3 µg/mL respectively. The antioxidant activity and enzymes inhibitory capacity of WEER were close, and comparable to the capacity demonstrated by the standards. The amount of sixteen compounds was identified from EEER. Numerous phytochemicals, including cynaroside, p-coumaric acid, cosmosiin, caffeic acid, and quinic acid, were quantitatively determined using the LC-MS/MS method. This clearly indicates that phenolic- and flavonoid-rich E. rauwolffii may have potential in the management of glaucoma, Alzheimer’s disease, diabetes, cardiovascular, and cancer disorders. Full article

The increasing demand for sustainable pest management has positioned essential oils (EOs) as viable bio-based alternatives to synthetic pesticides. This study investigates the insecticidal potential of Haplopappus foliosus EO, a Chilean endemic medicinal plant, against Drosophila melanogaster as a key toxicological model for fruit fly control. Chemical characterization identified 56 compounds, with 4-terpineol (27.27%) and α-bisabolol (10.40%) as the primary constituents, marking the first report of α-bisabolol in this species. To enhance bioavailability and overcome EO volatility, a nanoemulsion was developed, achieving an exceptionally small and stable particle size of 2.10 nm that remained consistent for over 90 days. Nanoencapsulation significantly optimized the EO’s efficacy, reducing the median lethal concentration (LC₅₀) from 120.26 µg/mL to a potent 54.57 µg/mL. While in vitro assays showed the free oil as a more potent acetylcholinesterase (AChE) inhibitor, molecular docking confirmed the high affinity of 4-terpineol and α-bisabolol for the enzyme’s active site, elucidating the neurotoxic mechanism at a molecular level. In silico analysis predicted a favorable human safety profile within GHS classes 4 and 5. Overall, this stable nanoformulation represents a sustainable biotechnological strategy for agricultural pest management, leveraging the synergistic effects and enhanced delivery of natural products. Full article

Myrciaria floribunda is a plant found in the Northeast region of Brazil with several insecticidal properties that remain little explored. In this sense, this study aims to investigate the harmful effects of essential oil (EO) from M. floribunda leaves against Sitophilus zeamais, an important corn pest. The EO was applied in toxicity tests by fumigation, contact, and ingestion, as well as in in vitro assays to evaluate its effects on the activity of the enzymes α-amylase, trypsin, and acetylcholinesterase. Chromatographic analysis of the oil revealed (E)-caryophyllene (56.41%), viridiflorol (4.02%) and α-selinene (3.85%) as the main compounds. The essential oil (EO) showed fumigation toxicity, with an LC₅₀ of 3.2 μL/L of air, and (E)-caryophyllene with an LC₅₀ of 3.97 μL/L of air. The EO inhibited insect feeding, altering growth rate and feed conversion efficiency starting at 62.5 μL/g. In this study, an increase in amylase and acetylcholinesterase (AChE) activity was observed. This increase in AChE activity may cause an imbalance in the nervous system, leading to insect death. Thus, the EO of M. floribunda may serve as an alternative for the control of S. zeamais in stored corn and help prevent significant post-harvest losses for farmers. Full article

Given the established interplay between oxidative stress, cholinergic dysfunction, and metabolic imbalance in cognitive decline, this study investigated the multifunctional potential of three red macroalgae from the Madeira Archipelago (Asparagopsis taxiformis, Grateloupia lanceola, and Nemalion elminthoides) using a sequential biorefinery approach. Marine algae represent a sustainable source of functional food ingredients due to their rich content in bioactive compounds and their compatibility with low-impact production systems. Protein, ethanolic (phenolic-rich), and polysaccharide fractions were obtained through direct extraction and scalable biorefinery processing. Antioxidant activity was evaluated using ORAC, DPPH, FRAP, and FIC assays, while functionality relevant to human health was assessed through acetylcholinesterase, butyrylcholinesterase, and α-glucosidase inhibition. Protein extracts, particularly from N. elminthoides, exhibited strong hydrogen atom transfer-based antioxidant capacity, whereas ethanolic extracts demonstrated multifunctional activity, combining radical scavenging, metal chelation, and enzyme inhibition associated with neuroprotective and glycemic-regulation potential. Polysaccharide fractions contributed mainly to iron chelation and reducing capacity. Correlation analyses highlighted the complementary nature of antioxidant and bioactivity assays. Overall, these findings support the potential of Madeira red macroalgae as functional food ingredients and emphasize the importance of optimized biorefinery strategies to maximize nutritional and health-related benefits. Full article

Background/Objectives: Cholinergic dysfunction plays a central role in memory impairment, yet trihexyphenidyl (THP)-based paradigms remain less explored than scopolamine-based models. This study aimed to characterize a THP-induced cholinergic challenge in a two-trial Y-maze with a 24 h interval and to compare the effects of donepezil and tacrine on recall-phase exploratory allocation. Methods: Male Wistar rats (n = 9/group) were studied in a validation phase including saline, THP 5 mg/kg, and THP 10 mg/kg groups, followed by an intervention phase including control, THP 10 mg/kg, donepezil 1 and 3 mg/kg + THP, and tacrine 3 and 5 mg/kg + THP groups. All treatments were administered intraperitoneally (i.p.). Acquisition- and recall-phase behavior was analyzed. Recall outcomes included arm times, arm entries, the novel-to-familiar arm time ratio (U/K time ratio), the novel-to-familiar arm entry ratio (U/K entry ratio), discrimination indices and time-per-entry indices. Data were analyzed by one-way ANOVA; Tukey’s post hoc test was used in the validation experiment, whereas Dunnett’s test was used in the intervention experiment for comparisons against THP 10. Results: THP at 10 mg/kg produced a robust recall-phase phenotype, with increased familiar-arm exploration, reduced novel-arm exploration and lower normalized indices. Under THP challenge, donepezil was associated with clearer effects at 3 mg/kg, whereas tacrine displayed a broader dose-dependent profile, with the strongest shift in recall-phase exploratory allocation toward the novel arm observed at 5 mg/kg. Conclusions: THP 10 mg/kg produced a robust recall-phase exploratory phenotype in a 24 h two-trial Y-maze paradigm. Under THP challenge, donepezil and tacrine were associated with shifts in recall-phase exploratory allocation. These findings support the potential utility of THP-based paradigms for studying cholinergic disruption in Y-maze settings, while direct comparison with scopolamine-based models remains to be established. Full article

The Morus genus comprises several tree species whose fruits are used in human nutrition, while the leaves and roots are used in traditional medicine. The aim of this study was to highlight the antioxidant, cholinesterase inhibitory, and neuroprotective effects of hydroalcoholic extracts from Morus alba (MAE) and Morus nigra (MNE) leaves. RP-UHPLC-PDA analysis of extracts revealed the presence of polyphenols in higher quantities in MNE extract compared to MAE. Both extracts demonstrated antioxidant properties in the hydroxyl radical scavenging and lipid peroxidation inhibition assays. MNE exhibited a superior antioxidant capacity compared to MAE; the IC₅₀ values for the inhibition of plasma lipid oxidation assay were 25.31 ± 2.54 µg/mL for MNE and 29.85 ± 0.97 µg/mL for MAE. Both extracts showed cholinesterase inhibitory activity. The IC₅₀ values for acetylcholinesterase inhibition were 24.34 ± 0.86 µg/mL for MNE and 46.87 ± 2.16 µg/mL for MAE. The inhibitory potency of MNE was comparable to that of galantamine, which was used as standard. Both extracts reversed, in a dose-dependent manner, the scopolamine-induced cognitive impairment and behavioural alterations in scopolamine-treated zebrafish (Danio rerio) as evaluated by the Y-maze test, novel tank diving test, and novel object recognition test. 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

In this study, the rank of multifaceted activity of catechin (C), epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG) and epigallocatechin-3-gallate (EGCG) was addressed. Their antioxidant activity was determined by the differential pulse voltammetry (DPV), whereas their ability to inhibit angiotensin-converting enzyme (ACE) activity, acetylcholinesterase activity (AChE), and formation of the advanced glycation end-products (AGEs) was performed in a model system to show their importance against hypertension, Alzheimer-type dementia, and diabetic’s complication, respectively. The order of the antioxidant potential of catechins in comparision to gallic acid (GA) was EGCG > ECG > EC > EGC ≈ C > GA, whereas the order of the ACE inhibitory activity was EGCG > ECG > EGC > EC > C, thus indicating the importance of the structure–activity relationship. The correlation between IC₅₀ for ACE inhibition of catechins and their antioxidant activity had the value r = −0.60. The order of the AChE enzyme inhibitory activity was EGCG ≈ EGC > ECG > EC > C, and the weak positive correlation between IC₅₀ and the first anodic peak potential (E_pa1) values was noted (r = 0.67). The ranking of the anti-AGE activities was EGCG ≈ ECG > EGC > EC > C, and a negative correlation between the inhibitory activity of catechins against AGE formation and their antioxidant activity was r = −0.82, whereas a positive correlation (r = 0.88) was noted between their first anodic peak potential (E_pa1) values. The provided results expand our knowledge on the multifaceted activity of catechins, indicating EGCG and ECG as the most active antioxidants against inhibition of ACE and AChE as well as towards AGE formation. Full article

Oxidative stress and inflammation are interconnected pathological processes involved in the progression of neurodegenerative, cardiovascular, and metabolic diseases, highlighting the need for multifunctional therapeutic agents targeting multiple pathways. In this study, two novel hybrid compounds were designed and synthesized in three steps by conjugating butylated phenolic moieties derived from butylated hydroxytoluene and p-coumaric acid with proline and γ-aminobutyric acid (GABA). The aim was the combination of antioxidant, anti-inflammatory, and cytoprotective properties within a single molecular framework. The compounds were evaluated using a comprehensive panel of in vitro and in vivo assays to assess antioxidant, metal-reducing, iron-chelating, antiglycation, anti-inflammatory, and acetylcholinesterase inhibitory activities. Both compounds exhibited significant antioxidant activity, with compound 2 demonstrating superior radical scavenging ability against DPPH, ABTS·⁺ and hydrogen peroxide (IC₅₀ 86 μM, 25 μM and 104 μM, respectively), enhanced ferric-reducing capacity (up to 91% of trolox activity), and strong iron-chelating activity (61.3%). Compound 2 also showed potent inhibition of lipid peroxidation (IC₅₀ 17.5 μM) and moderate antiglycation effects (44%), indicating substantial cytoprotective potential. Furthermore, both compounds selectively inhibited COX-2 over COX-1 and demonstrated moderate lipoxygenase inhibition, while compound 2 exhibited significant in vivo anti-inflammatory activity (53%), exceeding that of ibuprofen. Moderate acetylcholinesterase inhibition was also observed. In summary, the results confirm the design rationale, indicating that compound 2 could be further optimized as a multi-targeting molecule directed against oxidative stress- and inflammation-mediated conditions. Full article

DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies. Full article

Marine biofouling remains a major challenge for maritime industries, affecting submerged structures and vessels worldwide. The long-standing reliance on biocidal coatings, together with their documented environmental impacts, has led to increasingly restrictive regulations and an urgent demand for environmentally compatible antifouling (AF) solutions. This study evaluates the AF potential and toxicological profile of two nucleoside analogues, hypoxanthine arabinoside (1′) and 2′-deoxyinosine (2′), selected based on the previously reported non-lethal AF activity of the naturally occurring nucleosides adenosine and 2′-deoxyadenosine from cyanobacteria. Both analogues inhibited the growth of Navicula sp. by approximately 60% without inducing mortality and significantly reduced settlement of Mytilus galloprovincialis plantigrades, with EC₅₀ values of 5.50 µM (1′) and 8.54 µM (2′), and no lethality detected (LC₅₀ > 200 µM). At near-EC₅₀ concentrations, both compounds increased acetylcholinesterase and tyrosinase activities, supported by molecular docking results, suggesting involvement of neurotransmission- and byssal formation-related pathways. Proteomic analysis revealed compound-specific molecular responses. No lethal effects were observed in non-target organisms (LC₅₀ > 32 µM for A. amphitrite and LC₅₀ > 50 µM for A. salina), and environmental fate modelling predicted low bioaccumulation and rapid degradation. Overall, substitution of the amino group by a carbonyl group preserved AF efficacy without increasing toxicity, highlighting nucleosides as promising low-toxicity AF agents. Full article

Alzheimer’s disease is a progressive neurodegenerative disorder marked by declining cognitive function. While early-stage treatment focuses on acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) activity increases as the disease progresses, contributing to cholinergic deficits and neuroinflammation. This shift in enzyme dominance presents a compelling rationale for developing BChE-specific inhibitors as a potential therapeutic avenue. This study explores small, three-membered rings, scaffolds offering potential for interaction with the enzyme’s active site, as building blocks for novel BChE inhibitors. Employing a computational approach based on quantum–chemical multiligand simultaneous molecular docking, we virtually fitted these compounds into the BChE active site to predict binding affinity and key interactions. Our calculations extend beyond simple shape matching by incorporating accurate electronic properties, leading to more reliable predictions of binding strength and stability. The goal was not immediate identification of potent inhibitors, but a systematic assessment of how these rings interact with BChE. This foundational knowledge will inform the design and synthesis of larger, more complex molecules with enhanced binding affinity and selectivity, ultimately aiming to develop compounds to inhibit BChE activity and potentially slow Alzheimer’s progression. Full article

Neuroinflammation is determinant in the progression of neurodegenerative diseases. One of the main mechanisms underlying this process involves the persistent activation of glial cells. Persistent activation of glial cells induces proinflammatory transcription factors and the release of cytokines, chemokines, and reactive oxygen species that exacerbate cellular dysfunction. This neurotoxic environment promotes neuronal death, while the products of cellular damage feed back into glial activation, establishing a self-sustaining pathogenic cycle that drives neurodegeneration. Alkaloids present in Amaryllidaceae plants support the use of this resource in folk medicine, displaying potent effects as acetylcholinesterase inhibitors and allosteric modulators of nicotinic receptors (nAChR). In this study, a murine microglial cell (IMG) model of LPS-induced inflammation was used to evaluate the involvement of α7 and α4β2 nAChRs in glioprotection and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine (OHDA). GC-MS analysis revealed differences in the alkaloid profile between in vitro cultures with fructose and wild-type Rhodophiala pratensis. Homolycorine-type, norbelladine-type and crinine-type alkaloids produced in vitro reduced LPS-induced inflammation (5 µg/mL), possibly via α7 and α4β2 nAChRs, and showed a protective effect against OHDA-induced oxidative stress (1–3 µg/mL) and inhibited AChE and BuChE (24–78 µg/mL). Full article

Modern lifestyles characterized by reduced physical activity and changing eating habits have contributed to a global rise in obesity. This research examined the effects of a diet rich in linoleic acid combined with physical exercise using a TreadWheel system in Drosophila melanogaster. The flies were fed diets with varying linoleic acid concentrations from the larval stage through to day 15 of adulthood. A diet containing 45.9 mg/mL of linoleic acid improved eclosion rates, body weight, and biochemical markers such as glycogen, cholesterol, and hydrogen peroxide levels, as well as citrate synthase and acetylcholinesterase activities in sedentary flies. Conversely, flies that consumed linoleic acid and underwent 15 days of exercise on the TreadWheel showed increased weight, lactate, glycogen, cholesterol, nitric oxide levels, and acetylcholinesterase activity. These results suggest that a 15-day regimen of linoleic acid intake combined with physical exercise on the TreadWheel enhances muscle parameters in D. melanogaster, serving as an alternative animal model for nutrition and exercise research. Full article