AChE Inhibitory Activity Research Articles

Aqueous extract of Spirulina exerts neuroprotection in an experimental model of Alzheimer sporadic disease in mice induced by Streptozotocin.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes gradual memory loss and cognitive impairment. Intracerebroventricular injections of streptozotocin (ICV-STZ) have been used as an experimental model of sporadic Alzheimer's disease (SAD) because they produce deficits in brain insulin signaling, oxidative stress, neuroinflammation, and neurodegeneration, resulting in cognitive decline and memory impairment. Spirulina platensis (SPI) is a nutraceutical with anti-inflammatory, antioxidant, and neuroprotective properties. The objective of this work was to study the effects of SPI on cognitive deficits and neuronal damage in mice submitted to the experimental model of SAD induced by ICV-STZ. Male Swiss mice (25-35g) received ICV-STZ (3mg/Kg) bilaterally on days 1 and 3, SPI (50 and 100mg/Kg, o.p.) or vehicle (saline) was administered 2h after the second surgery, and once a day for 16 days. SPI treatment prevented working, episodic, spatial, and aversive memory deficits. Locomotor activity was not altered. ICV-STZ caused an increase in MDA, nitrite, and superoxide anion, while decreasing GSH. SPI treatment protected against GSH increase in the prefrontal cortex and hippocampus, and inhibited AChE activity in the prefrontal cortex. SPI prevented astrogliosis and microgliosis induced by ICV-STZ. These findings highlight the therapeutic potential of SPI for the treatment of SAD, indicating that its neuroprotective action is linked to antioxidant, anti-inflammatory, and AChE inhibitory activity.

Chemical Constituents and AChE Inhibitory Activities of Four Soil-Derived Streptomyces

Chemical Constituents and AChE Inhibitory Activities of Four Soil-Derived Streptomyces

Isolation of Bacillus altitudinis 5-DSW with Protease Activity from Deep-Sea Mineral Water and Preparation of Functional Active Peptide Fractions from Chia Seeds.

In this study, we successfully isolated Bacillus strains with high protease activity from deep-sea mineral water in Korea and used them to obtain functional peptide fractions from chia seeds. The obtained Bacillus strains showed a high similarity of 99% with B. altitude with a long rod type (named B. altitudinis 5-DSW) and high protease activity at 40 °C, and 70% of the activity remained even at 70 °C. The defatted chia seed protein (15-50 kDa) was treated with crude protease from B. altitudinis 5-DSW and digested into small peptides below 20 kDa. The obtained chia seed peptides showed 3 times and 1.5 times higher antioxidant activity in DPPH and ABT radical scavenging assays, respectively. Moreover, chia seed peptides showed enhanced AChE inhibitory activity with an IC50 value of 14.48 ± 0.88 μg/mL and BChE inhibition activity with an IC50 value of 10.90 ± 0.80 μg/mL. Our results indicate that the newly isolated B. altitudinis 5-DSW and chia seed protein hydrolysates have potential applications in biotechnology and functional food development, enhancing the nutritional quality and value-added utilization of chia byproducts.

AChE inhibitory activity of N-substituted natural galanthamine derivatives

Galanthamine derivatives are known for their AChE inhibitory activity. Among them, galanthamine has been approved for treatment of Alzheimer’s disease. N-Acetylnorgalanthamine (narcisine) and N-(2′-methyl)allylnorgalanthamine (the most potent natural AChE inhibitor of galanthamine type) were synthetized using N-norgalanthamine as a precursor. The NMR data described previously for narcisine were revised by two-dimensional 1H–1H and 1H–13C chemical shift correlation experiments. AChE inhibitory assays showed that N-acetylnorgalanthamine and N-formylnorgalanthamine (with previously unknown activity) are 4- and 43-times, respectively, less potent than galanthamine. In vitro (AChE inhibitory) and in silico (docking, ADME) assays and comparison of N-(2′-methyl)allylnorgalanthamine with galanthamine prove that this molecule is a very promising natural AChE inhibitor (33-times more potent than galanthamine) which further in vivo studies would provide better estimation about its applicability as a drug.

Melatonin intervention to prevent nanomaterial exposure-induced damages: A systematic review and meta-analysis of in vitro and in vivo studies.

Given its antioxidant, anti-inflammatory, and antiapoptotic properties, melatonin (MEL), a health-caring food to improve sleep disorders, is hypothesized to protect against nanomaterial exposure-induced toxicity. However, the conclusion derived from different studies seemed inconsistent. A meta-analysis of all available preclinical studies was performed to examine the effects of MEL on nanomaterial-induced damages. Eighteen relevant studies were retrieved through searching five electronic databases up to December 2023. The meta-analysis showed that relative to control, MEL treatment significantly increased cell viability (standardized mean difference [SMD = 1.27]) and alleviated liver function (lowered AST [SMD = -3.89] and ALT [SMD = -5.89]), bone formation (enhanced BV/TV [SMD = 4.13] and lessened eroded bone surface [SMD = -5.40]), and brain nerve (inhibition of AChE activity [SMD = -3.60]) damages in animals. The protective mechanisms of MEL against damages caused by nanomaterial exposure were associated with its antiapoptotic (decreased Bax/Bcl-2 ratio [SMD = -4.50] and caspase-3 levels [dose <100 μM: SMD = -3.66]), antioxidant (decreased MDA [in vitro: SMD = -2.84; in vivo: SMD = -4.27]), and anti-inflammatory (downregulated TNF-α [in vitro: SMD = -5.41; in vivo: SMD = -3.21] and IL-6 [in vitro: SMD = -5.90; in vivo: SMD = -2.81]) capabilities. In conclusion, our study suggests that MEL should be supplemented to prevent damages in populations exposed to nanomaterials.

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.

Rapid identification of chemical components and screening of acetylcholinesterase inhibitors from Dalbergia odorifera based on mass defect and diagnostic ion filtering strategy, affinity ultrafiltration, and liquid chromatography-tandem mass spectrometry.

Dalbergia odorifera is a natural product rich in pharmacological ingredients, but the comprehensive characterization and rapid profiling of active components remain a challenge. Thus, an integrated data mining and identification strategy was exploited to efficiently identify the chemical constituents and screen acetylcholinesterase inhibitors (AChEIs) through affinity ultrafiltration and ultra-high-performance liquid chromatography-mass spectrometry (AUF-UHPLC-MS). As a result, polygonal mass defect filtering, diagnostic product ions, and neutral loss rules were created for rapid structural classification and component identification. A total of 140 flavonoids were tentatively characterized, including 41 isoflavonoids, 23 flavanones, 21 isoflavans, 19 flavones and flavonols, 13 neoflavonoids, 11 isoflavanones, seven flavone glycosides, and five chalcones. Subsequently, six natural AChEIs including tectorigenin, fisetin, dalbergin, pterostilbene, isoliquiritigenin, and biochanin A were screened out using AUF-UHPLC-MS and molecular docking. Meanwhile, the AChE inhibitory activities of the six compounds were assessed in vitro, tectorigenin, fisetinand, and dalbergin have moderate inhibitory activity. In conclusion, a novel strategy for systematic characterization and further screening of active compounds in natural products was established, which provides a material basis for quality control of Dalbergia odorifera.

Modulation of Human Acetylthiocholine Esterase Activity by Novel Fused Pyrimidine Derivatives: In vitro, Theoretical and ADMET Studies

Pyrimidine compounds have medicinal and biological activities as previously reported. In this work, two novel fused pyrimidine compounds were synthesized, fused pyrazolo–pyrimidine compound was synthesized by cyclization of 5-amino-4-cyano-1-phenyl pyrazole with propionic acid in the presence of POCl3, and the other fused pyrrole–pyrano-pyrimidine compound was synthesized by cyclization of ethyl(E)-N-(3-cyano-4-(4-(dimethylamino)phenyl)-7-methyl-4,5,6,7-tetrahydropyrano[2,3-b] pyrrole-2-yl) formimidate with hydrazine hydrate, in methanol. These fused pyrimidine compounds were characterized by FT-IR and 1H NMR. The effect of these compounds was studied on the activity of the human neurotransmission enzyme acetylthiocholine esterase AChE. Results indicated that these compounds significantly inhibited AChE activity at concentrations of 10-11 M. Michalis-Menton showed mixed noncompetitive inhibition of AChE activity. In conclusion, newly synthesized compounds could be promising derivatives for enhancing cholinergic neurotransmission. Among the other derivatives, derivative 4 formed H-bond interactions with key amino acid residues Tyr334, and Asp72, whereas the other electrostatic interactions formed with Tyr334, Phe330, Ile287, Tyr121, Arg289, Trp279, Gly335, and Phe288. In the case of derivatives 9, similar binding interactions with active pockets of 2ACE were observed due to the high homology of the binding site residues. In addition, we examined ADMET properties with the help of online databases to search for possible drug similarity of synthesized compounds 4 and 9 and revealed that both molecules were compatible with Lipinski's five rules.

Intergenerational effects of low-dose graphene oxide exposure during pregnancy and lactation on mouse neurobehavior, reproduction and development

Graphene oxide (GO), a promising biomedical nanomaterial, has attracted increasing attention regarding its potential hazards to environment and health. However, data on its multigenerational toxicity in mammals are scarce, especially regarding GO exposure during pregnancy and lactation. In this study, we investigated the effects of low-dose (0.01–1 mg/L) GO exposure during pregnancy and lactation on reproduction, development and neurobehavior in mice through a multigenerational approach. There were no significant differences in the duration of pregnancy, litter size or survival index of the offspring between the maternal mice treated with GO and those in the control group. However, a significantly altered sex ratio was observed in F1 mice exposed to 0.01 mg/L GO. Additionally, alterations in anxiety state and decreased swimming velocity were observed in maternal mice treated with 0.01 and 1 mg/L GO. The effects of GO on neurobehavior seemed to be intensified in F1 mice, as evidenced by increased stress sensitivity, altered anxiety, decreased learning and memory, and inhibited AChE activity. Although some neurobehaviors returned to normal in F2 mice, anxiety-like behavior, increased antioxidant levels and an atrophic liver were observed in the GO 1 group. Furthermore, increases in the movement velocity and distance of F2 mice were observed in GO 0.01 group. These findings provide valuable data for evaluating the transgenerational risks associated with GO exposure among mammals.

The Synergistic Effect of Lemongrass Essential Oil and Flometoquin, Flonicamid, and Sulfoxaflor on Bemisia tabaci (Genn.) (Hemiptera: Aleyrodidae): Insights into Toxicity, Biochemical Impact, and Molecular Docking.

The whitefly, Bemisia tabaci (Genn.), is one of the most dangerous polyphagous pests in the world. Eco-friendly compounds and new chemical insecticides have gained recognition for whitefly control. In this study, the toxicity and biochemical impact of flometoquin, flonicamid, and sulfoxaflor, alone or combined with lemongrass essential oil (EO), against B. tabaci was studied. In addition, a molecular docking study was conducted to assess the binding affinity of the tested compounds to AchE. Based on the LC values, the descending order of the toxicity of the tested compounds to B. tabaci adults was as follows: sulfoxaflor > flonicamid > flometoquin > lemongrass EO. The binary mixtures of each of the tested compounds with lemongrass EO exhibited synergism in all combinations, with observed mortalities ranging from 15.09 to 22.94% higher than expected for an additive effect. Sulfoxaflor and flonicamid, alone or in combination with lemongrass EO, significantly inhibited AchE activity while only flonicamid demonstrated a significant impact on α-esterase, and none of the tested compounds affected cytochrome P450 or GST. However, the specific activity of P450 was significantly inhibited by the lemongrass/sulfoxaflor mixture while α-esterase activity was significantly inhibited by the lemongrass/flometoquin mixture. Moreover, the lemongrass EO and all the tested insecticides exhibited significant binding affinity to AchE with energy scores ranging from -4.69 to -7.06 kcal/mol. The current findings provide a foundation for utilizing combinations of essential oils and insecticides in the integrated pest management (IPM) of B. tabaci.

Dehydration, Rehydration and Thermal Treatment: Effect on Bioactive Compounds of Red Seaweeds Porphyra umbilicalis and Porphyra linearis.

The nutritional and bioactive value of seaweeds is widely recognized, making them a valuable food source. To use seaweeds as food, drying and thermal treatments are required, but these treatments may have a negative impact on valuable bioactive compounds. In this study, the effects of dehydration, rehydration, and thermal treatment on the bioactive compounds (carotenoids, phycobiliproteins, total phenolic content (TPC), total flavonoids content (TFC)), antioxidant (ABTS and DPPH radical scavenging activities) and anti-Alzheimer's (Acetylcholinesterase (AchE) inhibitory activities, and color properties of Porphyra umbilicalis and Porphyra linearis seaweeds were evaluated. The results revealed significant reductions in carotenoids, TPC, TFC, and antioxidant activities after the seaweeds' processing, with differences observed between species. Thermal treatment led to the most pronounced reductions in bioactive compound contents and antioxidant activity. AchE inhibitory activity remained relatively high in all samples, with P. umbilicalis showing higher activity than P. linearis. Changes in color (ΔE) were significant after seaweeds' dehydration, rehydration and thermal treatment, especially in P. umbilicalis. Overall, optimizing processing methods is crucial for preserving the bioactive compounds and biological activities of seaweeds, thus maximizing their potential as sustainable and nutritious food sources or as nutraceutical ingredients.

Synthesis, In Vitro Biological Evaluation and Molecular Modeling of Benzimidazole-Based Pyrrole/Piperidine Hybrids Derivatives as Potential Anti-Alzheimer Agents.

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.

Insecticidal, antifeedant and acetylcholinesterase inhibitory activity of sesquiterpenoids derived from eudesmane, their molecular docking and QSAR

This work evaluated the insecticidal, antifeedant and AChE inhibitory activity of compounds with eudesmane skeleton. The insecticidal activity was tested against larvae of Drosophila melanogaster and Cydia pomonella, the compounds 3 and 4 were the most active (LC50 of 104.2 and 106.7 μM; 82.0 and 84.4 μM, respectively). Likewise, the mentioned compounds were those that showed the highest acetylcholinesterase inhibitory activity, with IC50 of 0.26 ± 0.016 and 0.77 ± 0.016 μM, respectively. Enzyme kinetic studies, as well as molecular docking, show that the compounds would be non-competitive inhibitors of the enzyme. The antifeedant activity on Plodia interpunctella larvae showed an antifeedant index (AI) of 99% at 72 h for compounds 16, 27 and 20. The QSAR studies show that the properties associated with the polarity of the compounds would be responsible for the biological activities found.

Variation of the essential oil components of Citrus aurantium leaves upon using different distillation techniques and evaluation of their antioxidant, antidiabetic, and neuroprotective effect against Alzheimer’s disease

Citrus fruit essential oil is considered one of the widely studied essential oils while its leaves attract less attention although being rich in nearly the same composition as the peel and flowers. The leaves of bitter orange or sour orange (Citrus aurantium L.) were extracted using three different techniques namely; hydrodistillation (HD), steam distillation (SD), and microwave-assisted distillation (MV) to compare their chemical composition. The three essential oil samples were analyzed through GC/FID and GC/MS analyses. The samples were tested in vitro using different antioxidant techniques (DPPH, ABTS, CUPRAC, FRAP, PBD, and MCA), neuroprotective enzyme inhibitory activities (acetylcholine and butyl choline enzymes), and antidiabetic activities (α-amylase and α-glucosidase). The results showed that thirty-five volatile ingredients were detected and quantified. Monoterpenes represented the most abundant class in the three essential oils followed by sesquiterpenes. C. aurantium essential oil carried potential antioxidant activity where SD exhibited the highest antioxidant activity, with values arranged in the following order: FRAP (200.43 mg TE/g), CUPRAC (138.69 mg TE/g), ABTS (129.49 mg TE/g), and DPPH (51.67 mg TE/g). SD essential oil also presented the most potent α-amylase (0.32) inhibition while the MV essential oil showed the highest α-glucosidase inhibition (2.73 mmol ACAE/g), followed by HD (2.53 mmol ACAE/g), and SD (2.46 mmol ACAE/g). The SD essential oil exhibited the highest BChE and AChE inhibitory activities (3.73 and 2.06 mg GALAE/g), respectively). Thus, bitter orange essential oil can act as a potential source of potent antioxidant, antidiabetic, and neuroprotective activities for future drug leads.

Study on the preparation and enzyme inhibitory activity of polyphenols from Sargassum pallidum.

This study aimed to obtain a high yield and purity of Sargassum pallidum polyphenol extracts (SPPE) and study its enzyme activity. Fresh Sargassum pallidum seaweed was selected for optimization of ultrasound-assisted extraction (UAE) conditions and purification conditions using macroporous resin and Sephadex LH20 to obtain SPPE. The SPPE was characterized using UPLC-QTOF-MS/MS and α-amylase, α-glucosidase, tyrosinase, and AchE inhibitory activity were determined. The maximum extraction rate of SPPE was 7.56 mg GAE/g and the polyphenol purity reached 70.5% after macroporous resin and Sephadex LH-20 purification. A total of 50 compounds were identified by UPLC-QTOF-MS/MS. The IC50 values of SPPE were 334.9 μg/mL, 6.290 μg /mL, 0.834 mg /mL and 0.6538 mg /mL for α-amylase, α-glucosidase, tyrosinase and AchE, respectively. Molecular docking technology further revealed the effects of SPPE on the above enzymes. This study provided information on the potential hypoglycemic, whitening and anti-Alzheimer's disease biological activities of SPPE, which had guiding significance for the purification and development of other seaweed polyphenols.

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

A Series of Biguanide Ligands and Their Cu(II) Complexes: Cholinesterase Inhibitory and Antimicrobial Properties.

In this work, a series of biguanide hydrochloride salts and their Cu(II) complexes were synthesized and screened for their acetyl/butyryl choline esterase inhibitory and antimicrobial properties. The structures of the synthesized compounds were characterised by common spectroscopic and analytical methods. Biguanide compounds showed considerably lower inhibitory activity compared to the reference drugs donepezil and galantamine. On the other hand, complexation of the biguanide compounds with Cu(II) resulted in dramatic increase in the inhibitory activity. The Cu(II) complexes showed AChE inhibitory activity with the IC50 values of 21.29±0.95-82.53±0.20 μM and those values are comparable to that of donepezil (IC50 : 18.54±1.03 μM). The synthesised compounds were also screened for their antimicrobial activity towards gram positive (+) and gram negative (-) bacteria. Compounds (12.50 mg/mL) showed important antibacterial properties with inhibition zones of 8-28 mm diameter against gram-positive and gram-negative microorganisms. Compounds A03 and A08 exhibited more antimicrobial properties towards E. coli than standard antibiotics amikacin and gentamicin.

A Study on the Inhibition of AChE Activity by Ethanolic Extract of Tibet Wild Gymnadenia crassinervis and Its Protective and Reparative Effects on Aβ25−35‐Induced Cell Injury

A Study on the Inhibition of AChE Activity by Ethanolic Extract of Tibet Wild <i>Gymnadenia crassinervis</i> and Its Protective and Reparative Effects on A<i>β</i>₂₅₋₃₅‐Induced Cell Injury

One flask cascade approach to a complex pyrano[2,3-c]pyrazole-pyrazolone hybrid heterocyclic system and its initiatory neurobiological profiling.

A one-pot multicomponent approach towards a hybrid heterocyclic pyrano[2,3-c]pyrazole-pyrazolone framework involving tandem Knoevenagel condensation, sequential intermolecular 1,6-Michael addition, and 6-endo dig cyclization between diynones and pyrazolones, mediated by DBU, has been discovered. This process embodies several green and sustainable chemistry features. Preliminary bioactivity profiling of the new chemical entities indicates neuroprotective and AChE inhibitory activities.

Guvacoline in betel nuts directly binds to and inhibits AChE activity, lowering ACh levels released by neurons

This paper investigates guvacoline, a compound found in betel nut, and its activity on acetylcholine level. Betel nuts are the chewable seeds of plant used in Chinese traditional medicine. It is commonly used all over southern Asia and the east African seaboard, being the fourth most commonly used drug in the world. It is known for being carcinogenic for throat cancer. Immediate symptoms of betel nut chewing indicate activation of the parasympathetic system, in which acetylcholine and acetylcholinesterase is involved. This paper predicts that guvacoline, found in areca nuts, increases free acetylcholine levels released from neurons by allosterically binding to acetylcholinesterase inhibiting it.