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.
OBJECTIVE: 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.
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.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.

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.

BACKGROUND: As the cholinesterase theory is a prominent hypothesis underlying our current understanding of Alzheimer\'s disease (AD), the goal of this study was to compose functional vegan lunchtime soups with potential health benefits in the prevention of AD (in the context of cholinesterase inhibition).
METHODS: The potential of 36 edible plant raw materials in terms of acetyl- and butyrylcholinesterase inhibition was investigated using a 96-well microplate reader. The most promising ingredients were combined to obtain 18 palatable vegetable soup recipes with 6 dominant flavor, appearance, and aroma variants. To shortlist candidates for in-depth analysis and potential consideration in industrial production, our team performed a sensory analysis of the soups.
RESULTS: The white boletus soup exhibited the highest potential for cholinesterase inhibition, further bolstered by the inclusion of other ingredients known for their elevated capacity to inhibit both AChE and BChE. Ingredients such as blackthorn (Prunus spinosa), garlic, and white potato contributed significantly to this inhibitory effect (nearly 100% of AChE inhibition). Notably, intriguing results were also observed for asparagus soup, despite the fact that the inhibitory potential of asparagus itself is negligible compared to other raw materials. The success of the asparagus soup lies in the meticulous selection of various ingredients, each contributing to its overall effectiveness. It was observed that mushroom soups scored the highest in this respect, while the team members\' response to nettle soup was the least favorable.
CONCLUSIONS: The outcomes of our study should serve as a catalyst for further exploration of this important research domain. Our current research focuses on deeper insights into the potential of comprehensive meal options. Furthermore, the synergy/antagonism/non-interaction between respective soup ingredients as well as elements of individual soups\' chemical composition is a very interesting topic currently under our intensive scientific investigation.

Alzheimer\'s disease (AD), is a neurodegenerative disorder that escalates with time, exerting a significant impact on physical and mental health and leading to death. The prevalence of AD is progressively rising along with its associated economic burden and necessitates effective therapeutic approaches in the near future. This review paper aims to offer an insightful overview of disease pathogenesis, current FDA-approved drugs, and drugs in different clinical phases. It also explores innovative formulations and drug delivery strategies, focusing on nanocarriers and long-acting medications (LAMs) to enhance treatment efficacy and patient adherence. The review also emphasizes preclinical evidence related to nanocarriers and their potential to improve drug bioavailability, pharmacokinetics, and pharmacodynamics parameters, while also highlighting their ability to minimize systemic side effects. By providing a comprehensive analysis, this review furnishes valuable insights into different pathophysiological mechanisms for future drug development. It aims to inform the development of treatment strategies and innovative formulation approaches for delivering existing molecules in Alzheimer\'s disease, ultimately striving to improve patient compliance.

In this study, new indol-fused pyrano[2,3-d]pyrimidines were designed and synthesized. These products were obtained in moderate to good yields and their structures were assigned by NMR, MS, and IR analysis. Afterwards, the biological important of the products was highlighted by evaluating in vitro for α-glucosidase inhibitory activity as well as acetylcholinesterase (AChE) inhibitory activity. Eleven products revealed substantial inhibitory activity against α-glucosidase enzyme, among which, two most potent products 11d,e were approximately 93-fold more potent than acarbose as a standard antidiabetic drug. Besides that, product 11k exhibited good AChE inhibition. The substituents on the 5-phenyl ring, attached to the pyran ring, played a critical role in inhibitory activities. The biological potencies have provided an opportunity to further investigations of indol-fused pyrano[2,3-d]pyrimidines as potential anti-diabetic agents.

Alzheimer\'s disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided.

The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N\'-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC50 = 0.056 µM, while the IC50 for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC50 value was 9.01 µM compared to that for quercetin, with IC50 = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme.

Alzheimer\'s disease (AD) is a neurological disorder that affects millions of people worldwide. There are currently no cures for AD, although various drugs are used to manage the symptoms and reduce the disease\'s progression. AChE inhibitors such as rivastigmine, donepezil, galantamine, and the NMDA glutamate receptor antagonist memantine are currently FDA-approved drugs used in the treatment of AD. Recently, naturally derived biological macromolecules have shown promising results in the treatment of AD. Several biological macromolecules derived from natural sources are in various stages of preclinical and clinical trials. During the literature search, it was observed that there is a lack of a comprehensive review that particularly focuses on the role of naturally derived biological macromolecules (protein, carbohydrates, lipids, and nucleic acids) in the treatment of AD and the structure-activity relationship (SAR) approach for understanding the medicinal chemistry perspective. This review focuses on the SAR and probable mechanisms of action of biological macromolecules derived from natural sources for the treatment of AD, including peptides, proteins, enzymes, and polysaccharides. The paper further addresses the therapeutic possibilities of monoclonal antibodies, enzymes, and vaccines for the treatment of AD. Overall, the review provides insight into the SAR of naturally derived biological macromolecules in the treatment of AD. The ongoing research in this field holds great promise for the future development of AD treatment and provides hope for individuals affected by this devastating disease.Communicated by Ramaswamy H. Sarma.

A liquid crystal-based assay (LC) was developed to monitor paraoxon by incorporating a Cu2+ -coated substrate and the inhibitory effect of paraoxon with acetylcholinesterase (AChE). We observed that thiocholine (TCh), a hydrolysate of AChE and acetylthiocholine (ATCh), interfered with the alignment of 5CB films through a reaction between Cu2+ ions and the thiol moiety of TCh. The catalytic activity of AChE was inhibited in the presence of paraoxon due to the irreversible interaction between TCh and paraoxon; consequently, no TCh molecule was available to interact with Cu2+ on the surface. This resulted in a homeotropic alignment of the liquid crystal. The proposed sensor platform sensitively quantified paraoxon with a detection limit of 2.20 ± 0.11 (n = 3) nM within a range of 6 to 500 nM. The specificity and reliability of the assay were verified by measuring paraoxon in the presence of various suspected interfering substances and spiked samples. As a result, the sensor based on LC can potentially be used as a screening tool for accurate evaluation of paraoxon and other organophosphorus compounds.