Potent Acetylcholinesterase Inhibitors Research Articles

Exploring potential inhibitors of acetylcholinesterase, lactate dehydrogenases, and glutathione reductase from Hagenia abyssinica (Bruce) J.F. Gmel. based on multi-target ultrafiltration-liquid chromatography-mass spectrometry and molecular docking.

Parasitic infections impose a significant burden on public health worldwide. European pharmacopoeia records and ethnopharmacological studies indicate that Hagenia abyssinica (Bruce) J.F. Gmel. has traditionally been used to treat a variety of parasitic infections, while the potential antiparasitic compounds remain ambiguous. Acetylcholinesterase (AChE), lactate dehydrogenases (LDH), and glutathione reductase (GR) are the key target enzymes in the survival of parasites. The aim of our work was to screen antiparasitic compounds targeting AChE, LDH, and GR from H. abyssinica. Ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) combined with molecular docking was used in this study. Therein, the alamarBlue® and Ellman's methods were employed to reveal the antitrypanosomal effect and AChE inhibitory activity. Meanwhile, the UF-LC-MS was carried out to screen the potential active compounds from H. abyssinica. Subsequently, molecular docking was performed to evaluate the binding mechanisms of these active compounds with AChE, LDH, and GR. Finally, the AChE inhibitory activity of potential inhibitors was detected in vitro. H. abyssinica exhibited significant antitrypanosomal and AChE inhibitory activity. Corilagin, brevifolin carboxylic acid, brevifolin, quercetin, and methyl ellagic acid were recognized as potential AChE inhibitors by UF-LC-MS, while methyl brevifolin carboxylate was identified as AChE, LDH, and GR multi-target inhibitor, with binding degree ranged from 20.96%-49.81%. Molecular docking showed that these potential inhibitors had a strong affinity with AChE, LDH, and GR, with binding energies ranging from -6.98 to -9.67 kcal/mol. These findings were further supported by the observation that corilagin, quercetin, brevifolin carboxylic acid, and methyl brevifolin carboxylate displayed significant AChE inhibitory activity compared with the positive control (gossypol, 0.42 ± 0.04 mM), with IC50 values of 0.15 ± 0.05, 0.56 ± 0.03, 0.99 ± 0.01, and 1.02 ± 0.03 mM, respectively. This study confirms the antiparasitic potential of H. abyssinica, supporting the traditional use of H. abyssinica in local ethnopharmacology to treat parasites. At the same time, corilagin, brevifolin carboxylic acid, brevifolin, quercetin, methyl ellagic acid, and methyl brevifolin carboxylate exert their anti-parasitic effects by inhibiting AChE, LDH, and GR, and they are expected to be natural lead compounds for the treatment of parasitic diseases.

Benzamide Trimethoprim Derivatives as Human Dihydrofolate Reductase Inhibitors—Molecular Modeling and In Vitro Activity Study

Human dihydrofolate reductase (hDHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule (TMP) as a model compound in our search for a new class of hDHFR inhibitors. We incorporated an amide bond, a structural element typical of netropsin, a ligand that binds selectively in the minor groove of DNA, into the molecules of TMP analogs. In this work, we present previously obtained and evaluated eleven benzamides (JW1–JW8; MB1, MB3-MB4). Recently, these compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). JW8 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. All the benzamides were active against hDHFR, with IC50 values ranging from 4.72 to 20.17 µM, and showed activity greater than TMP (55.26 µM). Quantitative results identified the derivatives JW2 and JW8 as the most promising. A molecular modeling study demonstrates that JW2 interacts strongly with the key residue Gly-117, while JW8 interacts strongly with Asn-64 and Arg-70. Furthermore, JW2 and JW8 demonstrate the ability to stabilize the hDHFR enzyme, despite forming fewer hydrogen bonds with the protein compared to reference ligands. It can be concluded that this class of compounds certainly holds great promise for good active leads in medicinal chemistry.

Discovery of novel cholinesterase inhibitors easily crossing the blood-brain barrier via structure-property relationship investigation: Methylenedioxy-cinnamicamides containing tertiary amine side chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 μmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72 ± 93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Synthesis and biological activities of pyridine N-oxide bearing 5-aminoisoxazoles as potential acetylcholinesterase and monoamine oxidase inhibitors for Alzheimer's disease

Synthesis and biological activities of pyridine N-oxide bearing 5-aminoisoxazoles as potential acetylcholinesterase and monoamine oxidase inhibitors for Alzheimer's disease

Synthesis and Evaluation of Aminothiazole Hybrids as Potential Acetylcholinesterase Inhibitors

This study aimed to synthesize aminothiazole derivatives with 1,3,4-oxadiazole moiety and evaluated their acetylcholinesterase (AChE) and antioxidant activity in order to check their potency against Alzheimer's disease. Inhibition screening against AChE indicated that synthesized derivatives expressed well to moderate AChE inhibitory activity in vitro. Of the examined synthetic compounds (3a-i), compound 3d expressed the best inhibition with IC50-0.35 µM. The antioxidant activity of all the synthesized compounds was also analyzed by the DPPH assay. Finally, in molecular docking analysis, the best docking score was displayed by the most active compound 3d supported the in vitro inhibition results. Compound 3d emerged to be promising lead for the further development of anti- Alzheimer’s drugs.

Synthesis of Novel Hydrazide-Hydrazone Compounds and In Vitro and In Silico Investigation of Their Biological Activities against AChE, BChE, and hCA I and II.

The abnormal levels of the human carbonic anhydrase isoenzymes I and II (hCA I and II) and cholinesterase enzymes, namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are linked with various disorders including Alzheimer's disease. In this study, six new nicotinic hydrazide derivatives (7-12) were designed and synthesized for the first time, and their inhibitory profiles against hCA I, hCA II, AChE, and BChE were investigated by in vitro assays and in silico studies. The structures of novel molecules were elucidated by using spectroscopic techniques and elemental analysis. These molecules showed inhibitory activities against hCA I and II with IC50 values ranging from 7.12 to 45.12 nM. Compared to reference drug acetazolamide (AZA), compound 8 was the most active inhibitor against hCA I and II. On the other hand, it was determined that IC50 values of the tested molecules ranged between 21.45 and 61.37 nM for AChE and between 18.42 and 54.74 nM for BChE. Among them, compound 12 was the most potent inhibitor of AChE and BChE, with IC50 values of 21.45 and 18.42 nM, respectively. In order to better understand the mode of action of these new compounds, state-of-the-art molecular modeling techniques were also conducted.

Therapeutic Potential of Dicentrine in Human Disorders: A Review On Medicinal Importance and Pharmacological Activities of Aporphine Alkaloid

Backgrounds: Plants have always been an important source of food and drugs, in addition to their application in medical and cosmetic sectors. The popularity of herbal remedies has increased in many countries in recent decades. Herbal medicines contain numerous active phytocomponents with different biological activities. Alkaloid class phytochemicals have diverse chemical structures and pharmacological activities in nature. Additionally, Aporphinoids are an important class of plant secondary metabolites that have been used for the treatment of numerous human disorders for a long time in traditional medicine. Dicentrine is an aporphine class phytochemical isolated from numerous medicinal plants, including Actinodaphne sesquipedalis and Lindera megaphylla. Methods: The biological potential of dicentrine, an aporphine alkaloid derivative, has been described in the present work. Scientific data on dicentrine were collected here from different scientific databases and presented in this paper in order to know the biological importance of dicentrine in medicine for the treatment of human complications. Further, detailed pharmacological activities and scientific data on dicentrine were also analyzed in order to determine its therapeutic potential in medicine. Moreover, its analytical aspects were also described in this work to understand its separation and isolation methods. Results: The present work described the biological potential of dicentrine in medicine and its analytical aspects. It signified the biological potential of dicentrine in cancer, breast cancer, oral squamous cell carcinoma, lung adenocarcinoma, blood pressure, inflammatory disorders, hyperlipidaemia, arrhythmia, stomach muscle, and glomerulonephropathy. Further, its effectiveness in medicine was found to be mainly because of its antiplatelet, alpha 1-adrenoceptor, epidermal growth factor, antiprotozoal, larvicidal, antimicrobial, topoisomerase II, and acetylcholinesterase inhibitory potential. Moreover, other scientific data also signified its metabolism and pharmacokinetic parameters in terms of its analytical aspects in medicine. Conclusion: The present review gives us an updated summary of the scientific information for pharmacological activities and analytical aspects of dicentrine in medicine. It also signified the potential contribution of dicentrine in medicine for the development of a newer class of drug molecules for human disorders.

Amino-7,8-dihydro-4H-chromenone derivatives as potential inhibitors of acetylcholinesterase and butyrylcholinesterase for Alzheimer’s disease management; in vitro and in silico study

In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the management of Alzheimer’s disease (AD). The target compounds were evaluated against AChE and BChE in vitro, and 4k exhibited good potency against BChE (IC50 = 0.65 ± 0.13 µM) compared with donepezil used as a positive control. Kinetic studies revealed that compound 4k exhibited a competitive-type inhibition with a Ki value of 0.55 µM. Molecular docking and molecular dynamics simulations further supported the rationality of our design strategy, as 4k showed promising binding interactions with the active sites of BChE. Overall, our findings highlight the potential of amino-7,8-dihydro-4H-chromenone derivatives as promising candidates for developing novel therapeutics targeting cholinesterase in managing AD.

In Vitro Characterization and Rescue of VX Metabolism in Human Liver Microsomes.

Venomous agent X (VX) is an organophosphate acetylcholinesterase (AChE) inhibitor, and although it is one of the most toxic AChE inhibitors known, the extent of metabolism in humans is not currently well understood. The known metabolism in humans is limited to the metabolite identification from a single victim of the Osaka poisoning in 1994, which allowed for the identification of several metabolic products. VX has been reported to be metabolized in vitro by paraoxonase-1 and phosphotriesterase, although their binding constants are many orders of magnitude above the LD50, suggesting limited physiologic relevance. Using incubation with human liver microsomes (HLMs), we have now characterized the metabolism of VX and the formation of multiple metabolites as well as identified a Food and Drug Administration-approved drug [ethylenediaminetetraacetic acid (EDTA)] that enhances the metabolic rate. HLM incubation alone shows a pronounced increase in the metabolism of VX compared with buffer, suggesting that cytochrome P450-mediated metabolism of VX is occurring. We identified a biphasic decay with two distinct rates of metabolism. The enhancement of VX metabolism in multiple buffers was assessed to attempt to mitigate the effect of hydrolysis rates. The formation of VX metabolites was shown to be shifted with HLMs, suggesting a pathway enhancement over simple hydrolysis. Additionally, our investigation of hydrolysis rates in various common buffers used in biologic assays discovered dramatic differences in VX stability. The new human in vitro VX metabolic data reported points to a potential in vivo treatment strategy (EDTA) for rescue in individuals that are poisoned though enhancement of metabolism alongside existing treatments. SIGNIFICANCE STATEMENT: Venomous agent X (VX) is a potent acetylcholinesterase inhibitor and chemical weapon. To date, we do not possess a clear understanding of its metabolism in humans that would assist us in treating those exposed to it. This study now describes the human liver microsomal metabolism of VX and identifies ethylenediaminetetraacetic acid, which appears to enhance the rate of metabolism. This may provide a potential treatment option for human VX poisoning.

Combining Deep Learning and Structural Modeling to Identify Potential Acetylcholinesterase Inhibitors from Hericium erinaceus.

Alzheimer's disease (AD) is the most common type of dementia, affecting over 50 million people worldwide. Currently, most approved medications for AD inhibit the activity of acetylcholinesterase (AChE), but these treatments often come with harmful side effects. There is growing interest in the use of natural compounds for disease prevention, alleviation, and treatment. This trend is driven by the anticipation that these substances may incur fewer side effects than existing medications. This research presents a computational approach combining machine learning with structural modeling to discover compounds from medicinal mushrooms with a high potential to inhibit the activity of AChE. First, we developed a deep neural network capable of rapidly screening a vast number of compounds to indicate their potential to inhibit AChE activity. Subsequently, we applied deep learning models to screen the compounds in the BACMUSHBASE database, which catalogs the bioactive compounds from cultivated and wild mushroom varieties local to Thailand, resulting in the identification of five promising compounds. Next, the five identified compounds underwent molecular docking techniques to calculate the binding energy between the compounds and AChE. This allowed us to refine the selection to two compounds, erinacerin A and hericenone B. Further analysis of the binding energy patterns between these compounds and the target protein revealed that both compounds displayed binding energy profiles similar to the combined characteristics of donepezil and galanthamine, the prescription drugs for AD. We propose that these two compounds, derived from Hericium erinaceus (also known as lion's mane mushroom), are suitable candidates for further research and development into symptom-alleviating AD medications.

Suitability of human HepaRG cells and liver spheroids as in vitro model to investigate the bioactivation of the organothiophosphate pesticide parathion

Organophosphorus compounds (OP) constitute a large group of chemicals including pesticides and nerve agents. Organothiophosphate pesticides require cytochrome P450-mediated oxidative desulphuration in the liver to form corresponding oxons, which are potent inhibitors of the enzyme acetylcholinesterase (AChE). Human HepaRG cells are a promising tool to study liver-specific functions and have been shown to maintain drug metabolizing enzymes. This research describes for the first time the in vitro metabolic activation of an organothiophosphate to its active oxon by two different HepaRG cell-based models. Monolayer cultures and liver spheroids were exposed to the model OP parathion and the quantification of the corresponding oxon was performed with an AChE inhibition assay. Our results showed a time- and dose-dependent cytochrome P450 catalyzed bioactivation and a superior metabolism capacity of the monolayer HepaRG model in comparison with the liver spheroids. Finally, HepaRG cells can be assessed as a metabolically competent cell model intermediate between cell-free preparations and intact animals and as suitable to study OP metabolism in the human liver.

Identification of Potent Acetylcholinesterase Inhibitors as New Candidates for Alzheimer Disease via Virtual Screening, Molecular Docking, Dynamic Simulation, and Molecular Mechanics-Poisson-Boltzmann Surface Area Calculations.

Huperzine A (HUP) plays a crucial role in Alzheimer's therapy by enhancing cognitive function through increased cholinergic activity as a reversible acetylcholinesterase (AChE) inhibitor. Despite some limitations being seen in AChE inhibitors, ongoing research remains dedicated to finding innovative and more effective treatments for Alzheimer's disease. To achieve the goal of the discovery of potential HUP analogues with improved physicochemical properties, less toxic properties, and high biological activity, many in silico methods were applied. Based on the acetylcholinesterase-ligand complex, an e-pharmacophore model was developed. Subsequently, a virtual screening involving a collection of 1762 natural compounds, sourced from the PubChem database, was performed. This screening yielded 131 compounds that exhibited compatibility with the established pharmacophoric hypothesis. These selected ligands were then subjected to molecular docking within the active site of the 4EY5 receptor. As a result, we identified four compounds that displayed remarkable docking scores and exhibited low free binding energy to the target. These top four compounds, CID_162895946, CID_44461278, CID_44285285, and CID_81108419, were submitted to ADMET prediction and molecular dynamic simulations, yielding encouraging findings in terms of their pharmacokinetic characteristics and stability. Finally, the molecular dynamic simulation, cross-dynamic correlation matrix, free energy landscape, and MM-PBSA calculations demonstrated that two ligands from the selected ligands formed very resilient complexes with the enzyme acetylcholinesterase, with significant binding affinity. Therefore, these two compounds are recommended for further experimental research as possible (AChE) inhibitors.

Two new alkaloids from the roots of Cocculus hirsutus (L.) W. Theob

Two undescribed alkaloids, 15-carboxydihydroerysotrine (1) and (14 R)-4-methoxy-13,14-dihydrooxypalmatine (2), along with six known compounds, 1,6-didehydro-3,15,16-trimethoxy-9-methylerythrinanium (3), 8-oxytetrahydropalmatine (4), 20-hydroxyecdysone (5), makisterone A (6) turkesterone (7) and magnoflorine (8) were isolated from the root part of Cocculus hirsutus (L.) W. Theob. Their structures were established based on detailed analysis of NMR, UV-Vis, HRESIMS, and single-crystal XRD spectroscopic experiments. Compounds 3, 4 and 7 were reported for the first time from the genus Cocculus. All the compounds were analysed in silico to investigate their human acetylcholinesterase inhibition potential. This analysis revealed that compounds 1 and 8 interacted well with the selected protein, which suggested their further exploration as acetylcholinesterase inhibitors via in vitro and in vivo investigation.

Potential acetylcholinesterase inhibitors to treat Alzheimer's disease.

Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter acetylcholine has been related to the etiology of Alzheimer's disease. Acetylcholinesterase is an enzyme that breaks down acetylcholine to an inactive form and causes the death of cholinergic neurons. Conventional treatments were used but had less effectiveness. Therefore, there is a crucial need to identify alternative compounds with potential anti-cholinesterase agents and minimal undesirable effects. Fluoroquinolones and benzimidazole-benzothiazole derivatives offer antimicrobial, anti-inflammatory, anti-oxidant, anti-diabetic, and anti-Alzheimer activities. To enhance the chemical portfolio of cholinesterase inhibitors, a variety of fluoroquinolones and benzimidazole-benzothiazole compounds were evaluated against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and toxicology ADMET models were used for in-silico studies for both AChE and BChE enzymes to investigate possible binding mechanisms and drug-likeness of the compounds. The inhibitory effect of docked heterocyclic compounds was also verified in vitro against AChE and BChE enzymes. Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15, and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1 to 9) passed through the AChE inhibition assay and their IC50 values were calculated. The compound 1-ethyl-6-fluoro-7-(4-(2-(4-nitrophenylamino)-2-oxoethyl)piperazin-1-yl) -4-oxo-1,4 di-hydroquinoline-3-carboxylic acid and 2-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(3-bromobenzyl)-4-hydroxy-2H-thiochromene-3-carbohydrazide 1,1-dioxide (Z-9 and TBAF-6) showed the lowest IC50 values against AChE/BChE (0.37±0.02/2.93±0.03 µM and 0.638±0.001/1.31±0.01 µM, respectively) than the standard drug, donepezil (3.9±0.01/4.9±0.05 µM). During the in-vivo investigation, behavioral trials were performed to analyze the neuroprotective impact of Z-9 and TBAF-6 compounds on AD mouse models. The groups treated with Z-9 and TBAF-6 compounds had better cognitive behavior than the standard drug. This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole-benzothiazole) compounds improve behavioral and biochemical parameters, thus treating neurodegenerative disorders effectively.

Synthesis, in vitro biological evaluation and in silico molecular docking study of hydroxy‑quinoline based sulfonohydrazide derivatives as potential acetylcholinesterase and butyrylcholinesterase inhibitors

A series of hydroxy‑quinoline-based sulfonohydrazide derivatives (1–16) were synthesized and their structures were elucidated by using various spectroscopic tools including 1HNMR, 13CNMR and HREI-MS and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All synthesized derivatives showed the varied range of AChE and BuChE activities having IC50 values ranging from 0.20 ± 0.01 to 11.60 ± 0.20 µM (against AChE) and 0.80 ± 0.05 to 22.70 ± 0.30 µM (against BuChE) as compared to standard drug Donepezil (IC50 = 2.16 ± 0.12 µM & 4.5 ± 0.11 µM, respectively). Among the series, compounds 1, 8, and 10 were identified to be most potent, even more, active than standard drug having IC50 values of 0.40 ± 0.05, 0.20 ± 0.01, 0.70 ± 0.05 µM (against AChE) and 0.80 ± 0.05, 0.80 ± 0.05, 2.10 ± 0.10 µM (against BuChE) respectively. Based on the substitution pattern around the aryl ring, structure-activity relationship (SAR) analysis was conducted for all synthesized derivatives. Additionally, the molecular docking method was created to investigate the mechanism of interactions between the scaffolds that are most active and the active sites of specific AChE and BuChE enzymes.

Binding interactions and in silico ADME prediction of isoconessimine derivatives as potent acetylcholinesterase inhibitors

In pursuit of new acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease (AD), a series of ten previously synthesized isoconessimine compounds (7a-7j) was in silico investigated for their binding interactions with AChE and pharmacokinetics based on absorption, distribution, metabolism, and excretion (ADME) properties using molecular docking, ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) method and SwissADME tools. Docking experiments showed that all compounds bind within the active site gorge of AChE (PDB entry 1C2B), posing its aryloxy-substitutional ethyl group to catalytic site and conessine skeleton to peripheral anionic site. ONIOM interaction energy was used as an ONIOM score to improve docking score, and it ranked 7b as the most potent AChE inhibitor, in agreement with previous experiment. Residues, ASP74, TRP86, GLY122, GLU202, TRP286, GLU292, SER293, ILE294, TYR337, TYR341, and HIS447 were identified as important for the binding of the AChE-isoconessimine complex. The SwissADME investigation suggested that four compounds (7a, 7c, 7d and 7f) agree with the rules of drug-likeness. The steric and electronic effects on the aryloxy-substitutional ethyl group as important factors in the AChE inhibition were also discussed, which brings a better understanding of Alzheimer's disease drug development.

Neuroinflammation and Acetylcholinesterase Inhibitory Potentials of a Spiroketal-Enol Ether Polyyne Isolated from Artemisia pallens Wall. ex DC.

Artemisia pallens Wall. ex DC (Asteraceae) is cultivated for the production of high-value essential oil from its aerial biomass. In this study, the chemical composition of the root (crop-residue) essential oil was investigated for the first time, using column-chromatography, GC-FID, GC-MS, LC-QTOF, and NMR techniques, which led to the identification of twenty constituents, with isolation of (E)-2-(2',4'-hexadiynylidene)-1,6-dioxaspiro [4.5]dec-3-ene (D6). The D6 was evaluated in vitro for neuroinflammation and acetylcholinesterase inhibitory potential. It showed inhibition of neuroinflammation in a concentration-dependent manner with significant inhibition of pro-inflammatory cytokines (TNF-α and IL-6) in LPS-stimulated BV2 microglial cells. D6 did not have any significant effect on the viability of the cells at the therapeutic concentrations. D6 also has shown acetylcholinesterase inhibitory potential (51.90±1.19 %) at the concentration of log 106 nM. The results showed that D6 has a potential role in the resolution of neuroinflammation, and its acetylcholinesterase inhibitory potential directs further investigation of its role in the management of Alzheimer's disease-related pathogenesis.

Synthesis of a Rivastigmine and Insulin Combinational Mucoadhesive Nanoparticle for Intranasal Delivery.

Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer's disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions.

Therapeutic Potential and Pharmacological Activities of (+)-Nantenine in Medicine: An Aporphine Class Phytocomponent of Nandina domestica Thunberg.

Plant material and their derived byproducts have been used in medicine for the treatment of human disorders and complications. Plants give us a distinct class of natural compounds, commonly called secondary metabolites and better examples are the flavonoids, phenols, terpenoids, alkaloids, tannins, and carotenoids. Plant derived phytoproducts have been used for the treatment of human disorders in both traditional as well as modern medicine. Naturally occurring aporphines and their synthetic derivatives are well known in medicine for their pharmacological activities, including an affinity for dopaminergic, adrenergic and serotonergic receptors. (+)-nantenine is an aporphine alkaloid isolated from Nandina domestica and other plants. The aim of the present study is to analyze the biological potential and therapeutic effectiveness of nantenine in medicine. In the present work scientific information of nantenine for their medicinal uses and pharmacological activities have been collected from scientific databases such as Google, Google Scholar, PubMed, Scopus, and Science Direct . Scientific information of nantenine was further analyzed to know their health beneficial aspects in medicine. However, the detail pharmacological activity of nantenine has been discussed in the present work with its analytical aspects. Scientific data analysis described the medicinal importance and pharmacological activities of nantenine. Nantenine revealed adrenergic response, behavioral response, cardiovascular effect, vasorelaxant effect, acetylcholinesterase inhibitory potential, cytotoxicity, and biphasic tracheal relaxation. Present work also signified the biological potential of nantenine for their anti-inflammatory activity, anticonvulsant effect, antiserotonergic activities, anti-MDMA effect, antileishmanial activity, effect on histamine and serotonin, human 5-hydroxytryptamine (5-HT(2A)) and h5-HT(2B) receptors and isolated tissues. Further, the analytical techniques used for the separation, isolation and identification of nantenine have also been described in this work. The present scientific data describes the therapeutic potential and pharmacological activities of (+)-nantenine in medicine.

3D-QSAR-based pharmacophore modelling of quinazoline derivatives for the identification of acetylcholinesterase inhibitors through virtual screening, molecular docking, molecular dynamics and DFT studies

Alzheimer’s disease (AD) is a progressive neurological disorder responsible for the cognitive dysfunction and cognitive impairment in the patients. Acetylcholinesterase inhibitors (AChEIs) are used to treat AD however, these only provided symptomatic relief and more efficient drug molecules are desired for the effective treatment of the disease. In this article, ligand-based drug-designing strategy was used to develop and validate a field-based 3D-QSAR pharmacophore model on quinazoline-based AChEIs reported in the literature. The validated pharmacophore model (AAAHR_1) was used as a prefilter to screen an ASINEX database via virtual screening workflow (VSW). The hits generated were subjected to MM-GBSA to identify potential AChEIs and top three scoring molecules (BAS 05264565, LEG 12727144 and SYN 22339886) were evaluated for thermodynamic stability at the target site using molecular dynamic simulations. Additionally, DFT study was performed to predict the reactivity of lead molecules towards acetylcholinesterase (AChE). Thus, by utilising various computational tools, three molecules were identified as potent AChEIs that can be developed as potential drug candidates for the treatment of AD. Communicated by Ramaswamy H. Sarma