Two series of non-symmetrical bisquaternary pyridiniumaquinolinium and pyridiniumaisoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their ...inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as ambenonium dichloride, edrophonium bromide and experimental compound BW284C51.
A series of tacrineaebselen hybrids were synthesised and evaluated as possible multifunctional anti-Alzheimeras disease (AD) agents. Compound 6i, which is tacrine linked with ...5,6-dimethoxybenzod1,2selenazol-3(2H)-one by a six-carbon spacer, was the most potent acetylcholinesterase (AChE) and butylcholinesterase (BuChE) inhibitor, with IC50 values of 2.55 and 2.80 nM, respectively. Furthermore, this compound demonstrated similar hydrogen peroxide and peroxynitrite scavenging activity as ebselen by horseradish peroxidase assay and peroxynitrite scavenging activity assay, indicating that this hybrid is a good multifunctional drug candidate for the treatment of AD.
A series of berberineathiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and I2-amyloid (AI2) aggregation and as ...antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 mu M, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 mu M. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including AI2 aggregation inhibition and antioxidant properties.
Alzheimeras disease (AD) is a multifactorial disorder with several target proteins contributing to its etiology. In search for multifunctional anti-AD drug candidates, taking into account that the ...acetylcholinesterase (AChE) and beta-amyloid (AI2) aggregation are particularly important targets for inhibition, the tacrine and benzothiazole (BTA) moieties were conjugated with suitable linkers in a novel series of hybrids. The designed compounds (7aa7e) were synthesized and in vitro as well as in ex vivo evaluated for their capacity for the inhibition of acetylcholinesterase (AChE) and AI2 self-induced aggregation, and also for the protection of neuronal cells death (SHSY-5Y cells, AD and MCI cybrids). All the tacrineaBTA hybrids displayed high in vitro activities, namely with IC50 values in the low micromolar to sub-micromolar concentration range towards the inhibition of AChE, and high percentages of inhibition of the self-induced AI2 aggregation. Among them, compound 7a, with the shortest linker, presented the best inhibitory activity of AChE (IC50 = 0.34 mu M), while the highest activity as anti-AI242 self-aggregation, was evidenced for compound 7b (61.3%, at 50 mu M. The docking studies demonstrated that all compounds are able to interact with both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Our results show that compounds 7d and 7e improved cell viability in cells treated with AI242 peptide. Overall, these multi-targeted hybrid compounds appear as promising lead compounds for the treatment of Alzheimeras disease.
Neurotoxic pesticides are a group of chemicals that pose a severe threat to both human health and the environment. These molecules are also known to accumulate in the food chain and persist in the ...environment, which can lead to long-term exposure and adverse effects on non-target organisms. The detrimental effects of these pesticides on neurotransmitter levels and function can lead to a range of neurological and behavioral symptoms, which are closely associated with neurodegenerative diseases. Hence, the accurate and reliable detection of these neurotoxic pesticides and associated neurotransmitters is essential for clinical applications, such as diagnosis and treatment. Over the past few decades, acetylcholinesterase (AchE) biosensors have emerged as a sensitive and reliable tool for the electrochemical detection of neurotoxic pesticides and acetylcholine. These biosensors can be tailored to utilize the high specificity and sensitivity of AchE, enabling the detection of these chemicals. Additionally, enzyme immobilization and the incorporation of nanoparticles have further improved the detection capabilities of these biosensors. AchE biosensors have shown tremendous potential in various fields, including environmental monitoring, clinical diagnosis, and pesticide residue analysis. This review summarizes the advancements in AchE biosensors for electrochemical detection of neurotoxic pesticides and acetylcholine over the past two decades.
•This paper reviews the research status of acetylcholinesterase (AchE) biosensors.•Pesticides influence the neurotransmitters linked to neurodegenerative diseases.•AchE biosensors used for detecting pesticides and acetylcholine are reviewed.•Immobilizing AchE enhances biosensor performance, sensitivity, and selectivity.•AchE biosensor was used for environmental monitoring and clinical diagnosis.
Single-atom nanozymes (SAzymes), as novel nanozymes with atomically dispersed active sites, are of great importance in the development of nanozymes for their high catalytic activities, the maximum ...utilization efficiency of metal atoms, and the simple model of active sites. Herein, the peroxidase-like SAzymes with high-concentration Cu sites on carbon nanosheets (Cu–N–C) were synthesized through a salt-template strategy. With the densely distributed active Cu atoms (∼5.1 wt %), the Cu–N–C SAzymes exhibit remarkable activity to mimic natural peroxidase. Integrating Cu–N–C SAzymes with natural acetylcholinesterase and choline oxidase, three-enzyme-based cascade reaction system was constructed for the colorimetric detection of acetylcholine and organophosphorus pesticides. This work not only provides a strategy to synthesize SAzymes with abundant active sites but also gives some new insights for robust nanozyme biosensing systems.
Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. ...Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC sub(50) 0.10 kmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD.
The aim of this study was to characterize the effects of ESP-102 on the memory impairments and pathological changes induced by amyloid-b (Ab)1-42 peptide in mice. The ameliorating effect of ESP-102 ...on memory impairment was investigated using the passive avoidance and the Morris water maze tasks, and the pathological changes were identified by immunohistochemistry and western blotting. Ab1-42 peptide (3I14g/3I14l) was administered by intracerebroventricular injection. By the single administration of ESP-102 (100mg/kg, p.o), the memory impairment induced by Ab1-42 peptide was significantly attenuated (P<0.05). Moreover, ESP-102 (100mg/kg, p.o) significantly inhibited acetylcholinesterase (AChE) activity in the hippocampus compared to the Ab1-42 peptide-injected control group. In the subchronic treatment study, ESP-102 (50 or 100mg/kg/day, p.o) administration for seven days ameliorated the memory impairments induced by Ab1-42 peptide. Moreover, ESP-102 inhibited lipid peroxidation induced by Ab1-42 peptide in the hippocampus. Ab1-42-induced increases in the expression of GFAP (an astrocyte marker) and inducible nitric oxide synthase (iNOS) in the hippocampal region were also attenuated by ESP-102 treatment. These results suggest that the ameliorating effect of ESP-102 on Ab1-42 peptide-induced memory impairment is mediated via its AChE inhibitory, antioxidative, and/or anti-inflammatory activities. a-ordmSingle Ab injection into the cerebral ventricle causes memory impairment and neural damages. a-ordmAcute ESP-102 administration improves Ab-induced memory impairment. a-ordmSubchronic ESP-102 administration blocks Ab-induced inflammation and oxidative damages.
Amyloid b (Ab) is considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Mitochondrial and ER apoptotic pathways are considered to be involved in this process. Galantamine is ...an acetylcholinesterase (AChE) inhibitor widely used for patients with AD. In this study, we investigated the neuroprotective effects of galantamine on Ab sub(25-35)-induced apoptosis in PC12 cells and the underlying mechanisms. Exposure of PC12 cells to 20 kM Ab sub(25-35) caused significant cell viability loss and apoptosis, Ab aggregation, mitochondrial and ER morphological changes, as well as mitochondrial membrane potential dissipation, reactive oxygen species (ROS) production, intracellular calcium elevation, and cytochrome c release from mitochondria. Pretreatment with 10 kM galantamine for 24 h prior to Ab sub(25-35) exposure significantly reduced Ab sub(25-35)-induced apoptosis not only by preventing Ab aggregation, mitochondrial and ER morphological changes, mitochondrial membrane potential dissipation, ROS production, intracellular calcium elevation, and cytochrome c release, but also via reversing Bcl-2/Bax ratio and suppressing the activity of GADD153, Grp78/94, caspase-9, caspase-12, and caspase-3. All these data indicate that galantamine protects PC12 cells against Ab sub(25-35)-induced apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum (ER) stress.
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