Effect of an organophosphate insecticide on the behaviour and physiology of the spider Misumenops maculissparsus (Araneae: Thomisidae).

Pests in agriculture cause significant economic damage by reducing production and product quality. While pesticides can be an alternative for pest control, their use has a significant impact on both the environment and human health. Chlorpyrifos, a widely used pesticide, affects both target and non-target organisms, including spiders. In this study, we investigated whether Misumenops maculissparsus spiders at three developmental stages (J0, J2, and adults) recognize the presence of the insecticide and how it affects their enzymatic activity. The results indicated that only J0 was able to recognize the insecticide and avoided surfaces treated with it. On the other hand, J0 and adults exhibited reduced acetylcholinesterase (AChE) activity and the activity of antioxidant enzymes was affected by the treatment. Superoxide dismutase (SOD) increased significantly in J0, catalase (CAT) in all stages, glutathione S-transferase (GST) in J2, and glutathione peroxidase (GPx) in J2 and adults. Chlorpyrifos exposure did not increase reactive oxygen species or alter cellular populations in any model.

A Series of Novel 1-H-isoindole-1,3(2H)-dione Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: In Silico, Synthesis and In Vitro Studies.

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

Unusual norcucurbitacin glycosides from the roots of Siraitia grosvenorii.

Siraitia grosvenorii Swingle is one of the first approved medicine food homology species in China, and it has been used as a natural sweetener in the food industry and as a traditional medicine to relieve cough and reduce phlegm. However, many S. grosvenorii roots are discarded yearly, which results in a great waste of resources. Twelve undescribed norcucurbitacin-type triterpenoid glycosides, siraitiaosides A-L (1-12), and six known analogs (13-18) were isolated from the roots of S. grosvenorii. The structures of isolated norcucurbitacin glycosides were elucidated by comprehensive data analyses, including HRESIMS, UV, IR, NMR, ECD calculations, and X-ray crystallography analysis. Siraitiaosides A-E (1-5) featured an unusual 19,29-norcucurbitacin framework while siraitiaosides F-L (6-12) featured a rare 29-norcucurbitacin framework. Notably, compound 4 displayed moderate anti-acetylcholinesterase (AChE) activity with an IC50 of 21.0 µM, meanwhile, compounds 16 and 18 exhibited pronounced cytotoxic activities against MCF-7, CNE-1, and HeLa cancer cell lines with IC50 values of 2.1-15.2 µM. In silico studies showed that compound 4 bound closely to AChE with a binding energy of -5.04 kcal/mol, and compound 18 could tightly bind to PI3K, AKT1, ERK2, and MMP9 proteins that related to autophagy, apoptosis, migration/invasion, and growth/proliferation. In summary, the roots of Siraitia grosvenorii have potential medicinal values due to the multiple bioactive components.

Pharmacological evaluation and binding behavior of 4,4'-diamino-2,2'-stilbene disulfonic acid with metal ions using spectroscopic techniques.

Industrial and human activities contribute significantly to the environmental contamination of heavy metal ions (HMIs), which have detrimental effects on aquatic life, plants, and animals, causing major toxicological problems. The commercially available 4,4'-diamino-2,2'-stilbenedisulfonic acid (DSD) has been playing a vital role in the detection of heavy metal ions and has significantly inhibited a variety of cancer cells in numerous field of modern science. The current investigation aimed to ensure the detection of heavy metals ions from the environment and fluorescence imaging of DSD in the treatment of cancer cells. Fluorescence and UV-Visible spectroscopic analysis was performed to sense the selective behavior of the probe DSD with several heavy metal ions, including Fe2+, K1+, Co2+, Ni2+, Zn2+, Cd2+, Pb2+, Mn2+, Sn2+, and Cr3+. Furthermore, DSD was subjected to examine enzyme inhibition such as anti-Alzheimer, anti-inflammatory, antioxidant, anticancer, and antimicrobial activities in search of multifaceted drugs. Test compounds have demonstrated dose-dependent responses in the in-vitro enzyme inhibition assays for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), cyclooxygenase (COX), and lipoxygenase (LOX), as well as antioxidant [DPPH = 2,2-diphenyl-1-picrylhydrazyl and ABTS = 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid]. The DSD were shown to be more effective than the conventional medication galantamine in inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with an IC50 value of 12.18 and 20.87 µM, which is equivalent to the standard drug. The results obtained has revealed that DSD has the potential to become an effective sensor for the detection of Sn2+ ions over competing metal ions due to the inhibition of photo-induced electron transfer pathway (PET). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide tetrazolium) test, demonstrated that DSD had strong anticancer effects against the brain cancer cell line NIH/3T3, HeLa and MCF-7 with an IC50 value of 32.59, 15.31 and 96.46 µM respectively. The antimicrobial testing has shown that DSD outperforms the standard drug cefixime against Candida albicans and Pseudomonas aeruginosa, respectively. This study makes a substantial contribution to the ongoing search for efficient treatments for breast cancer.

Alstomaphylines A-K, monoterpenoid bisindole alkaloids from Alstonia macrophylla with AChE inhibitory activity and cytotoxicity.

Eleven undescribed monoterpenoid bisindole alkaloids, alstomaphyines A-K (1-11), along with three known analogues were isolated from the leaves and stem bark of the Alstonia macrophylla. Compounds 1-3 were unprecedented dimerization alkaloids incorporating a macroline-type motif with an ajmaline-type motif via a C-C linkage. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and CD exciton chirality method. Compounds 1-3 displayed potential inhibitory bioactivity against AChE with IC50 values of 4.44 ± 0.35, 3.59 ± 0.18, and 3.71 ± 0.23 µM, respectively. Enzyme kinetic study revealed compounds 1-3 as mixed competitive AChE inhibitors. Besides, compounds 8 and 12-14 exhibited better cytotoxicity against human cancer cell line HT-29 than cisplatin. Flow cytometry data revealed that compounds 8, 13, and 14 significantly induced the HT-29 cells arrest in G0/G1 phase in a concentration-dependent manner.

Walnut oil: a promising nutraceutical in reducing oxidative stress and improving cholinergic activity in an in vitro Alzheimer's disease model.

Improving the quality of life in elderly patients and finding new treatment options for neurological diseases such as Alzheimer's has become one of the priorities in the scientific world. In recent years, the beneficial effects and therapeutic properties of natural foods on neurological health have become a very remarkable issue. Walnut oil (WO) is a promising nutraceutical, with many phytochemicals and polyunsaturated fatty acids and is thought to be promising in the treatment of many neurological diseases and cognitive deficits, such as Alzheimer's disease (AD). Polyphenolic compounds found in WO enhance intraneuronal signaling and neurogenesis and improve the sequestration of insoluble toxic protein aggregates. The objective of this study was to investigate the potential protective and therapeutic effects of WO in a model of AD induced by retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). In order to achieve this, the experimental groups were formed as follows: Control group, WO group, Alzheimer's disease (AD) group, AD + WO applied group (AD + WO). WO supplementation almost significantly reduced oxidative stress in the ad model, providing 2-fold protection against protein oxidation. Additionally, WO showed a significant reduction in tau protein levels (2-fold), increased acetylcholine (ACh) levels (12%), and decreased acetylcholine esterase (AChE) activity (~50%). Since it has been known for centuries that WO does show any adverse effects on human health and has neuroprotective properties, it may be used in the treatment of AD as an additional nutraceutical to drug treatments.

Leaf and Flower Extracts from the Dwarf Elder (Sambucus ebulus): Toxicity and Repellence against Cosmopolitan Mosquito-Borne Diseases Vectors.

As there has been no scientific evidence of the bioactivity of Sambucus ebulus (Adoxaceae) extracts against insects, we chemically characterized S. ebulus leaves and flowers extracted in methanol and water. The crude extracts, phenolic compounds, and amino acids isolated were tested as larvicides against the fourth-instar larvae of Aedes albopictus and Culex pipiens (Diptera: Culicidae). To understand their mode of action, we evaluated the in vitro acetylcholinesterase (AChE) inhibitor effect of the crude extracts on the two mosquito larvae through a colorimetric method. Furthermore, the deterrent effect of the crude extracts against ovipositing Ae. albopictus females was assessed in the open field. Twelve phenylpropanoids and fourteen amino acids were detected in the extracts, with a prevalence of hydroxycinnamic acids and nonaromatic amino acids. The most toxic compound to Ae. albopictus larvae after 24 h was gallic acid, followed by the crude S. ebulus leaf extract; on Cx. pipiens, it was the crude flower extract. The AChE test showed higher inhibition on both mosquito species exerted by the leaf extract if compared to the flower extract, and it also deterred oviposition by Ae. albopictus females starting from the third day. The results indicated that vegetal extracts could effectively help in the integrated vector management of mosquitoes.

In silico molecular modeling and in vitro biological screening of novel benzimidazole-based piperazine derivatives as potential acetylcholinesterase and butyrylcholinesterase inhibitors.

New series of benzimidazole incorporating piperazine moieties in single molecular framework has been reported. The structures of the synthesized derivatives were assigned by 1H-NMR, 13C-NMR, and HR-MS techniques. The hybrid derivatives were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibition effect. All the synthesized analogs showed good to moderate inhibitory effect ranging from IC50 value 0.20 ± 0.01 µM to 0.50 ± 0.10 µM for acetylcholinesterase and from IC50 value 0.25 ± 0.01 µM to 0.70 ± 0.10 µM for butyrylcholinesterase except one that showed least potency with IC50 value 1.05 ± 0.1 µM and 1.20 ± 0.1 µM. The differences in inhibitory potential of synthesized compounds were due to the nature and position of substitution attached to the main ring. Additionally, molecular docking study was carried out for most active in order to explore the binding interactions established by ligand (active compounds) with the active residues of targeted AChE & BuChE enzyme.

Aqueous sage leave extract attenuates inflammation and oxidant-induced genotoxicity in human peripheral blood mononuclear cells.

Traditional medicine has used sage (Salvia officinalis L.) preparations for centuries to prevent and treat various inflammatory and oxidative stress-induced conditions. The aim of this in vitro study was to determine the bioactive properties of a sage leave extract obtained with environmentally friendly aqueous extraction and lyophilisation in primary human peripheral blood cells. To that end we measured the total phenolic and flavonoid content (TPC and TFC, respectively) with gas chromatography-mass spectrometry (GC-MS). Non-cytotoxic concentrations determined with the trypan blue assay were used to assess the antioxidant (DPPH, ABTS, and PAB assay), antigenotoxic (CBMN assay), immunomodulatory (IL-1ß and TNF-α), and neuroprotective effects (AChE inhibition). The extract contained high TPC (162 mg GAE/g of dry extract) and TFC (39.47 mg QE/g of dry extract) concentrations, while ß-thujone content was unexpectedly low (below 0.9 %). Strong radical-scavenging activity combined with glutathione reductase activation led to a decrease in basal and H2O2-induced oxidative stress and DNA damage. A decrease in TNF-α and increase in IL-1ß levels suggest complex immunomodulatory response that could contribute to antioxidant and, together with mild AChE inhibition, neuroprotective effects. Overall, this study has demonstrated that aqueous sage leave extract reduces the levels of thujone, 1,8-cineole, pinene, and terpene ketones that could be toxic in high concentrations, while maintaining high concentrations of biologically active protective compounds which have a potential to prevent and/or treat inflammatory and oxidative stress-related conditions.

Vegan and Vegetarian Soups Are Excellent Sources of Cholinesterase Inhibitors.

BACKGROUND: The cholinesterase theory stands as the most popular worldwide therapy for Alzheimer's disease (AD). Given the absence of a cure for AD, a plant-based diet has been repeatedly shown as positive in the prevention of AD, including exploring ready-made products in stores and the development of new functional foods. GOAL: This study compared the anti-acetyl- and butyrylcholinesterase activity of thirty-two Polish market soups and five newly formulated soups intended to be functional. Additionally, the research aimed to assess the significance of animal content, distinguishing between vegan and vegetarian options, in cholinesterase inhibition. MATERIALS AND METHODS: The anticholinesterase activity was investigated using a spectrophotometric method, and the inhibitory activity was expressed as % inhibition of the enzyme. The study categorized soups into three groups based on ingredients: those containing animal-derived components, vegetarian soups and vegan soups. RESULTS: Soups exhibited varying levels of activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), indicating differences in their compositions. Composition appeared to be the primary factor influencing anticholinesterase activity, as soups within each group showed significant variability in activity levels. While some commercial soups demonstrated notable anticholinesterase activity, they did not surpass the effectiveness of the optimized soups developed in the laboratory. Certain ingredients were associated with higher anticholinesterase activity, such as coconut, potato, onion, garlic, parsley and various spices and herbs. CONCLUSIONS: Vegetarian and vegan soups exhibited comparable or even superior anticholinesterase activity compared to animal-derived soups, highlighting the importance of plant-based ingredients. The study underscores the need for further research to explore the mechanisms underlying the anticholinesterase activity of soups, including the impact of ingredient combinations and processing methods.

Investigation of cholinesterase and α-glucosidase enzyme activities, and molecular docking and dft studies for 1,2-disubstituted cyclopentane derivatives with phenyl and benzyl units.

Six known products (4-9) were prepared from reaction of adipoyl chloride with 1,2,3-trimethoxybenzene according to the literature. From (2,3,4-trimethoxyphenyl)(2-(2,3,4-trimethoxyphenyl)cyclopent-1-en-1-yl)methanone (4) of them, four new 1,2-disubstituted cyclopentane derivatives (10-13) with phenyl and benzyl units were synthesized by reactions such as hydrazonation, catalytic hydrogenation and bromination. The obtained compounds 4-13 were examined for their in vitro inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glucosidase enzymes. All compounds 4-13 showed inhibition at nanomolar level with Ki values in the range of 45.53 ± 7.35-631.96 ± 18.88 nM for AChE, 84.30 ± 9.92-622.10 ± 35.14 nM for BChE, and 25.47 ± 4.46-48.87 ± 7.33 for α-Glu. In silico molecular docking studies of the potent compounds were performed in the active sites of AChE (PDB: 1E66), BChE (PDB: 1P0I), and α-glucosidase (PDB: 5ZCC) to compare the effect of bromine atom on the inhibition mechanism. The optimized molecular structures, HOMO-LUMO energies and molecular electrostatic potential maps for the compounds were calculated by using density functional theory with B3LYP/6-31 + G(d,p).

Functional Outcomes of Fluoroscopy-Guided Intra-articular Steroids in Lumbar Facet Arthropathy: A Retrospective Comparative Study of Dexamethasone Versus Triamcinolone Acetonide.

Introduction  Mechanical low back pain frequently originates from the lumbar facet joint (LFJ). Axial low back discomfort can result from osteoarthritis in the LFJ. Depending on the severity of LFJ degeneration, the effect of intra-articular (IA) LFJ corticosteroid injection may vary. For LFJ discomfort, IA block with steroids and local anaesthetics has also been utilised, with varying degrees of success. The main objective of this study was to assess the efficacy of IA steroid injections dexamethasone vs. triamcinolone acetonide for the treatment of LFJ syndrome and to compare functional outcome in terms of Visual Analog Scale (VAS) score, Modified Oswestry Disability Index (MODI) score, and short-form McGill Pain Questionnaire between the two groups. Methodology Dexamethasone 8 mg or triamcinolone acetonide 40 mg was given intra-articularly to 27 patients comprising group A and 33 patients comprising group B, respectively (total 60 patients). Before intervention and at one, three, and six months, observation was conducted using the VAS score, short-form McGill pain questionnaire, and MODI score. Results There was a significant difference between both the groups after the procedure with pain alleviation and functional improvement, more in the group that received triamcinolone acetonide. A significant difference was observed in all three parameters that assessed pain with differences more pronounced at six months. Conclusion Pain reduction and clinical outcomes were better among the group that received triamcinolone acetonide. Injection of a steroid alone is associated with its own side effects. When a lumbar transforaminal epidural injection is used to treat radiculopathy in the lumbar area, particulate medication (triamcinolone) is more effective than non-particulate medication (dexamethasone) with no known drug-related complications.

New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer's disease: design, synthesis, and biological evaluation.

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Design, synthesis and anti-Alzheimer's disease activity evaluation of C-3 arylated huperzine A derivatives.

A series of C-3 arylated huperzine A (HPA) derivatives (1-30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC50 = 1.205 ± 0.395 µM; 15, IC50 = 0.225 ± 0.062 µM) and butyrylcholinesterase (BChE inhibition: 2, IC50 = 8.598 ± 3.605 µM; 15, IC50 = 4.013 ± 0.068 µM), a feature not observed in huperzine A. Molecular docking results indicated that the introduction of aryl groups enhanced the affinity of the derivatives for the acyl-binding pocket of BChE, thereby limiting the hydrolysis of acetyl choline. However, these derivatives exhibited poor performance in cytotoxicity and neuroprotection assays.

Toxic effects of fenvalerate in tadpoles of Fejervarya limnocharis: a multiparametric study.

Pyrethroids are among the most widely used insecticides. Fenvalerate (FEN), a synthetic pyrethroid, is frequently used in domestic and agricultural settings to control insects which ultimately find its way into the aquatic ecosystems. The larval stages of amphibians, which are experiencing a rapid population decline, are spent in aquatic habitats, thus making them vulnerable to FEN exposure. The potential toxic effects of pyrethoids in general and FEN in particular are not well understood. The present study was carried out to assess the toxicity of FEN in tadpoles of Fejervarya limnocharis. FEN at different concentrations (0, 4, 5, 6, 7, and 8 mg/L) induced substantial lethal effects. The estimated LC50 values were 8.54, 6.73, 5.44, and 4.44 mg/L at 24, 48, 72, and 96 h respectively. Exposure to environmentally relevant sub-lethal concentrations delayed metamorphosis and reduced survivality. FEN was found to be genotoxic in erythrocyte micronucleus and comet assay. Further, sub-lethal concentrations of FEN adversely affected the antioxidant defense mechanism of the exposed individuals with parallel increase oxidative damage to membrane lipids. The swimming behavior in the form of startle response, swirl response, and total movements was decreased with a concomitant decrease in AChE activity. In addition, FEN exhibited significant cardiotoxicity by decreasing the cardiac rate of the exposed individuals. The present findings clearly indicate that FEN can cause significant toxicity to the tadpoles of F. limnocharis affecting their survival and fitness in the natural environment.

Thiamethoxam toxicity on the stingless bee Friesiomelitta varia: LC50, survival time, and enzymatic biomarkers assessment.

Bees play a crucial role as pollinating insects in both natural and cultivated areas. However, the use of pesticides, such as thiamethoxam, has been identified as a contributing factor compromising bee health. The current risk assessment primarily relies on the model species Apis mellifera, raising concerns about the applicability of these assessments to other bee groups, including stingless bees. In this study, we investigated the acute toxicity of thiamethoxam on the stingless bee Frieseomelitta varia by determining the average lethal concentration (LC50) and mean lethal time (LT50). Additionally, we evaluated the enzymatic profile of Acetylcholinesterase (AChE), Carboxylesterase-3 (CaE-3), and Glutathione S-Transferase (GST), in the heads and abdomens of F. varia after exposure to thiamethoxam (LC50/10). The LC50 of thiamethoxam was determined to be 0.68 ng ai/µL, and the LT50 values were 37 days for the control group, 25 days at LC50/10, and 27 days at LC50/100. The thiamethoxam significantly decreased the survival time of F. varia. Furthermore, the enzymatic profile exhibited differences in CaE3 activity within one day in the heads and ten days in the abdomen. GST activity showed differences in the abdomen after one and five days of thiamethoxam exposure. These findings suggests that the abdomen is more affected than the head after oral exposure to thiamethoxam. Our study provides evidence of the toxicity of thiamethoxam at both the cellular and organismal levels, reinforcing the need to include non-Apis species in pollinator risk assessments. and provide solid arguments for bee protection.

Indanone: a promising scaffold for new drug discovery against neurodegenerative disorders.

Indanone is a versatile scaffold that has a number of pharmacological properties. The successful development and ensuing approval of indanone-derived donepezil as a drug of choice for Alzheimer's disease attracted significant scientific interest in this moiety. Indanones could act as small molecule chemical probes as they have strong affinity towards several critical enzymes associated with the pathophysiology of various neurological disorders. Inhibition of these enzymes elevates the levels of neuroprotective brain chemicals such as norepinephrine, serotonin and dopamine. Further, indanone derivatives are capable of modulating the activities of both monoamine oxidases (MAO-A and -B) and acetylcholinesterase (AChE), and thus could be useful in various neurodegenerative diseases. This review article presents a panoramic view of the research carried out on the indanone nucleus in the development of potential neuroprotective agents.

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3ß for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3ß (GSK-3ß) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it. OBJECTIVES: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3ß and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3ß and AChE. METHODS: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger. RESULTS: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3ß and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3ß and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules. CONCLUSION: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3ß and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.

Computational identification of potential acetylcholinesterase (AChE) and monoamine oxidase-B inhibitors from Vitis vinifera: a case study of Alzheimer's disease (AD).

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that affects people aged 60 years and above. Yet, the discovery of potent therapeutic agents against this disease has no utmost progress and a number of drug candidates could not make it out of the clinical trials at varied stages. At the same time, the currently available anti-cholinesterase (AChE) and monoamine oxidase-B (MAO-B) for the treatment of AD can only improve the clinical symptoms while the recently approved immunotherapy agent "remains questionable. Thus, the need for novel therapeutic agents with the potential to treat the aetiology of the disease. Herein, this study sought to examine the potential of a number of bioactive compounds derived from Vitis vinifera as a promising agent against AChE and MAO-B. Using a computational approach via molecular docking 23 bioactive agents were screened against AChE and MAO-B, and the compounds with a binding score below that of the standard ligand were further subjected to drug-likeness and pharmacokinetic screening. Eight and thirteen of the studied agents optimally saturated the active pocket of the AChE and MAO-B respectively, forming principal interactions with a number of amino acids at the active pocket of the targets and among these compounds only rutin failed the drug-likeness test by violating four parameters while all showed moderate pharmacokinetics features. A number of Vitis vinifera-derived bioactive compounds show excellent inhibitory potential against AChE and MAO-B, and moderate pharmacokinetic features when compared to the reference ligand (tacrine). These compounds are therefore proposed as novel AChE and MAO-B inhibitors for the treatment of AD and wet-lab analysis is necessary to affirm their potency.

Synthesis of novel hybrids of 1,2,3-triazoles-hydrazone: targeting cholinesterases and Alzheimer's related genes.

Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer's activity. Materials & methods: All compounds were screened toward cholinesterases via the modified Ellman's method. The toxicity assay on SH-SY5Y cells was performed using the MTT assay, and the expression levels of GSK-3α, GSK-3ß, DYRK1 and CDK5 were assessed in the presence of compounds 6m and 6p. Results: 6m and 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase and butyrylcholinesterase inhibitory activity, respectively. 6m demonstrated no toxicity under tested concentrations on the SH-SY5Y cells and positively impacted neurodegenerative pathways. Notably, 6m displayed a significant downregulation in mRNA levels of GSK-3α, GSK-3ß and CDK5. Conclusion: The target compounds could be considered in developing anti-Alzheimer's disease agents.

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