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Acetylcholinesterase (AChE) plays an important role in the pathogenesis of neurodegenerative diseases by influencing the inflammatory response, apoptosis, oxidative stress and aggregation of pathological proteins. There is a search for new compounds that can prevent the occurrence of neurodegenerative diseases and slow down their course. The aim of this review is to present the role of AChE in the pathomechanism of neurodegenerative diseases. In addition, this review aims to reveal the benefits of using AChE inhibitors to treat these diseases. The selected new AChE inhibitors were also assessed in terms of their potential use in the described disease entities. Designing and searching for new drugs targeting AChE may in the future allow the discovery of therapies that will be effective in the treatment of neurodegenerative diseases.

Hesperidin, a natural flavanone glycoside predominantly found in citrus fruits, has gained attention for its wide-ranging biological activities, including potential insecticidal properties. Culex pipiens , commonly known as the northern house mosquito, is a major vector of several human pathogens, such as the West Nile virus and filariasis, making it a key target in the fight against vector-borne diseases. In this study, we evaluated the larvicidal activity of Hesperidin against Culex pipiens larvae, assessing its potential as an alternative to chemical insecticides. Hesperidin demonstrated potent larvicidal effects, with a lethal concentration 50 (LC 50 ) of 570.3 ± 0.04 µg/mL, outperforming the conventional insecticide Chlorpyrifos 588.3 ± 0.28 µg/mL in efficacy. Molecular docking simulations revealed a strong binding affinity between Hesperidin and crucial neuroreceptors in Culex pipiens , particularly acetylcholinesterase (AChE), a key enzyme involved in nerve signal transmission. The interaction between Hesperidin’s hydroxyl groups and the AChE enzyme’s active site suggests that AChE inhibition is the primary mechanism driving Hesperidin’s insecticidal action. These findings position Hesperidin as a promising, environmentally friendly alternative to synthetic insecticides. However, further research is needed to assess its toxicity to non-target organisms and optimize its formulation for broader application in mosquito control.

Little is known about the non-neuronal spermic cholinergic system, which may regulate sperm motility and the acrosome reaction initiation process. We investigated the presence of the key acetylcholine (ACh)-biosynthesizing enzyme, choline acetyltransferase (ChAT), and the acetylcholine-degrading enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and two ACh-receptors in human spermatozoa and seminal plasma. Fresh ejaculates were used for intra- and extracellular flow cytometric analysis of ChAT, AChE, BChE, and alpha-7-nicotinic and M1-muscarinic ACh-receptors in sperm. For determining the source of soluble enzymes, frozen seminal samples (n = 74) were selected on two bases: (1) from vasectomized (n = 37) and non-vasectomized (n = 37) subjects and (2) based on levels of alpha-glucosidase, fructose, or zinc to define sample subgroups with high or low fluid contribution from the epididymis and seminal vesicle, and prostate, respectively. Flow cytometric analyses revealed that ChAT was expressed intracellularly in essentially all spermatozoa. ChAT was also present in a readily membrane-detachable form at the extracellular membrane of at least 18% of the spermatozoa. These were also highly positive for intra- and extracellular BChE (>83%) and M1 (>84%) and α7 (>59%) ACh-receptors. Intriguingly, the sperm was negative for AChE. Analyses of seminal plasma revealed that spermatozoa and epididymides were major sources of soluble ChAT and BChE, whereas soluble AChE most likely originated from epididymides and seminal vesicles. Prostate had relatively minor contribution to the pool of the soluble enzymes in the seminal fluid. In conclusion, human spermatozoa exhibited a cholinergic phenotype and were one of the major sources of soluble ChAT and BChE in ejaculate. We also provide the first evidence for ChAT as an extracellularly membrane-anchored protein. Summary Sentence Human spermatozoa exhibit a predominantly cholinergic phenotype and are the main source of the soluble ChAT and BChE in seminal fluid.

Fagonia arabica L. is a widely used traditional medicinal herb. This study explored the flavonoid and phenolic acid content in the aerial parts of F. arabica , leading to the tentative identification of 42 compounds using Ultra-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass/Mass Spectrometry and analyzed with the phytochemical-focused RIKEN tandem mass spectral database (ReSpect) for identification based on authentic standards. The total phenolic and flavonoid content was measured in the ethyl acetate and butanol fractions. The flavonoid content in the ethyl acetate fraction was 101 ± 1.43 µg Rutin/mg, compared to 6.48 ± 0.29 µg rutin/mg in the butanol fraction. Similarly, the ethyl acetate fraction contained 199.14 ± 1.58 µg gallic acid/mg, while the butanol fraction had 47.69 ± 0.54 µg gallic acid/mg. Also, the study demonstrated the effectiveness of the different fractions of Fagonia arabica L. in inhibiting the butyrylcholinesterase enzyme, which is a key contributor to the progression of Alzheimer’s disease. At a concentration of 0.45 mg/mL, the ethyl acetate fraction showed the highest efficiency, inhibiting butyrylcholinesterase by 50% (IC 50 ). Based on the in vitro results, a molecular docking study suggested the selectivity of the tentatively identified compounds towards butyrylcholinesterase over acetylcholinesterase, as kaempferol-3- O -glucoside achieved the highest selectivity. This insight could inform potential modifications to enhance selectivity, which may be applied in the synthesis, semi-synthesis, and development of novel treatments for Alzheimer’s disease.

Decades of research have produced no effective method to prevent, delay the onset, or slow the progression of Alzheimer’s disease (AD). In contrast to these failures, acetylcholinesterase (AChE, EC 3.1.1.7) inhibitors slow the clinical progression of the disease and randomized, placebo-controlled trials in prodromal and mild to moderate AD patients have shown AChE inhibitor anti-neurodegenerative benefits in the cortex, hippocampus, and basal forebrain. CNS neurodegeneration and atrophy are now recognized as biomarkers of AD according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria and recent evidence shows that these markers are among the earliest signs of prodromal AD, before the appearance of amyloid. The current AChE inhibitors (donepezil, rivastigmine, and galantamine) have short-acting mechanisms of action that result in dose-limiting toxicity and inadequate efficacy. Irreversible AChE inhibitors, with a long-acting mechanism of action, are inherently CNS selective and can more than double CNS AChE inhibition possible with short-acting inhibitors. Irreversible AChE inhibitors open the door to high-level CNS AChE inhibition and improved anti-neurodegenerative benefits that may be an important part of future treatments to more effectively prevent, delay the onset, or slow the progression of AD.

In this study, a novel series of 1,2,4-triazolo[4,3- a ]quinoxalines containing a sulfonamide moiety was designed and synthesized through regioselective synthesis from 2 and/ 3-hydrazino-6-(pyrrolidin-1-ylsulfonyl)quinoxaline derivatives 5 and 7 . The structures of two isomers were confirmed and characterized by IR, 1 H NMR, 13 C NMR, and elemental analysis data. The synthesized 1,2,4-triazolo[4,3- a ]quinoxaline derivatives 8–13 were evaluated for their antidiabetic activities by targeting α-amylase and α-glucosidase, as well as for their anti-Alzheimer activity by targeting acetylcholinesterase (AChE) at a concentration of 100 µM. Structure-activity relationship (SAR) analysis was conducted for all analogs, emphasizing the nature of the substituent groups at position one of the triazole nucleus and the positioning of the sulfonamide moiety. For α-amylase and α-glucosidase activity, the designed compounds exhibited moderate to good activity, with inhibitory percentage values ranging from 21.85 ± 0.01% to 64.70 ± 0.02% and from 23.93 ± 0.01% to 75.36 ± 0.01%, respectively. The N -allyl-[1,2,4]triazolo[4,3- a ]quinoxalin-1-amine derivative 10a demonstrated the most significant inhibitory activity, with percentages of 64.70 ± 0.02% and 75.36 ± 0.01% against α-amylase and α-glucosidase, respectively, in comparison to acarbose (IP = 67.33 ± 0.01% and 57.79 ± 0.01%). Furthermore, the 1,2,4-triazolo[4,3- a ]quinoxaline derivatives 8–13 exhibited low to moderate inhibitory percentages against the acetylcholinesterase enzyme, except for the 1-methyl-[1,2,4]triazolo[4,3- a ]quinoxaline derivative 11b which demonstrated the highest inhibitory percentage of 44.78 ± 0.01%, compared to donepezil (IP = 67.27 ± 0.60%). Moreover, the promising derivative 10a demonstrated exceptional inhibitory activity, exhibiting IC 50 values of 3.46 ± 0.06 µM and 6.89 ± 0.09 µM against α-glucosidase and α-amylase, respectively, when compared to acarbose, which has IC 50 values of 4.27 ± 0.06 µM and 5.90 ± 0.09 µM. Finally, molecular docking simulations were performed for compound 10a within α-amylase (PDB: 2QV4) and α-glucosidase (PDB: 3W37), while compound 11b was analyzed within acetylcholinesterase (AChE) (PDB: 4EY7) to assess binding affinity and to explore the binding interactions with the active sites of the enzymes.

Currently prescribed medications for the treatment of Alzheimer's disease (AD) that are based on acetylcholinesterase inhibition only offer symptomatic relief but do not provide protection against neurodegeneration. There appear to be an intense need for the development of therapeutic strategies that not only improve brain functions but also prevent neurodegeneration. The oxidative stress is one of the main causative factors of AD. Various antioxidants are being investigated to prevent neurodegeneration in AD. The objective of this study was to investigate the neuroprotective effects of naringenin (NAR) against AlCl3+D-gal induced AD-like symptoms in an animal model. Rats were orally pre-treated with NAR (50 mg/kg) for two weeks and then exposed to AlCl3+D-gal (150 mg/kg + 300 mg/kg) intraperitoneally for one week to develop AD-like symptoms. The standard drug, donepezil (DPZ) was used as a stimulator of cholinergic activity. Our results showed that NAR pre-treatment significantly protected AD-like behavioral disturbances in rats. In DPZ group, rats showed improved cognitive and cholinergic functions but the neuropsychiatric functions were not completely improved and showed marked histopathological alterations. However, NAR not only prevented AlCl3+D-gal induced AD-like symptoms but also significantly prevented neuropsychiatric dysfunctions in rats. Results of present study suggest that NAR may play a role in enhancing neuroprotective and cognition functions and it can potentially be considered as a neuroprotective compound for therapeutic management of AD in the future.

Vitamin B1 (thiamine) plays an important role in human metabolism. It is essential for the proper growth and development of the body and has a positive effect on the functioning of the digestive, cardiovascular, and nervous systems. Additionally, it stimulates the brain and improves the psycho-emotional state. In vivo, vitamin B1 occurs in free form as thiamine or as its ester with phosphate residue(s), i.e., as mono-, di-, or triphosphate. It has been proven that supportive therapy with vitamin B1 can not only provide neuroprotection but also has a positive effect on advanced neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Wernicke–Korsakoff syndrome, or Huntington’s disease. This paper presents studies on the effect of free thiamine (T) and thiamine pyrophosphate (TPP) on the activity of acetylcholinesterase (AChE), which is an enzyme considered to play an important role in the therapies for neurodegenerative diseases, especially Alzheimer’s disease. The mechanisms of action of these compounds as potential inhibitors of AChE were evaluated using both experimental (enzymatic activity) as well as computational (molecular docking, molecular dynamics simulations, and MM-GBSA calculations) methods. The results of the current study indicate a non-competitive type of enzyme inhibition, in contrast to the previously published works suggesting a competitive one.

Mosquito-borne diseases remain a significant global public health challenge. This challenge is further exacerbated by the growing resistance of disease-vector species such as Culex pipiens to conventional insecticides. In this study, we present the design, synthesis, and biological assessment of a new series of thiophene-isoquinolinone hybrids as potential larvicides. Among the synthesized compounds, derivatives 5f, 6, and 7 showed significant larvicidal effectiveness against Culex pipiens larvae, with LC₅₀ values of 0.3, 0.1, and 1.85 µg/mL, respectively. Notably, all twelve thiophene-isoquinolinone derivatives were much more toxic than the reference organophosphate insecticide chlorpyrifos (LC₅₀ = 293.8 µg/mL), demonstrating the strength of these chemical structures. Interestingly, the synthetic intermediate compound 1a, a thiophene-based half-ester, exhibited the highest activity (LC₅₀ = 0.004 µg/mL), outperforming all final derivatives despite not being fully optimized. Mechanistic bioassays showed consistent neurotoxic symptoms that suggest a disruption of cholinergic function. Molecular docking and molecular dynamics simulations supported this observation, revealing strong and specific interactions with both acetylcholinesterase (AChE) and nicotinic acetylcholine receptors (nAChRs), which points to a possible dual-target mechanism. Density Functional Theory (DFT) calculations further confirmed the favorable electronic properties and reactivity of the active compounds. The structural variety within this series, along with consistently high potency, may lower the risk of cross-resistance and aid resistance management strategies through compound rotation or combination. Overall, these findings highlight thiophene-isoquinolinone hybrids as a promising option for developing next-generation larvicides that target neurophysiological pathways in insect vectors.

In the pursuit of therapeutic agents for Alzheimer’s disease (AD), this study employed a molecular hybridization strategy to design and synthesize substituted cinnamoyl piperidinyl acetates. A total of 17 novel derivatives were evaluated for their inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), key enzymes implicated in AD pathogenesis. Notably, compound 5b , featuring a 2-chloro substitution, emerged as the most potent AChE inhibitor (IC 50  = 19.74 ± 0.96 µM), while compound 5q , possessing a 4-ethoxy-3-methoxy moiety, demonstrated superior BChE inhibition (IC 50  = 13.49 ± 0.44 µM). Kinetic studies revealed mixed-type inhibition for compound 5b ( K i = 10.03 µM, K is = 36.16 µM), and molecular docking confirmed its stable interactions with AChE’s catalytic and peripheral anionic sites. These findings underscore the potential of cinnamoyl piperidinyl acetate derivatives as promising scaffolds for further optimization and development into effective AD therapeutics.