Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

Withanolide Profile and Acetylcholinesterase Inhibitory Activity of Two Argentinean Jaborosa Species.

Acetylcholinesterase (AChE) inhibitors are still an important option for managing symptoms of mild to moderate Alzheimer's disease. In this study, we aimed to evaluate the potential in vitro AChE inhibitory activity of two Argentinian endemic Solanaceae species, Jaborosa bergii and J. runcinata. UHPLC-DAD-HRMS metabolite profiling revealed the presence of withanolides in the active CH2Cl2 subextracts. Their fractionation led to the isolation and identification of two known spiranoid withanolides from J. runcinata and three new withanolides with a skeleton similar to that of trechonolide-type withanolides from J. bergii. The known compounds showed moderate AChE inhibitory activity, while the new ones were inactive.

Molecular modeling of multi-target analogs of huperzine A and applications in Alzheimer's disease.

CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.

A theoretical screening of phytochemical constituents from Millettia brandisiana as inhibitors against acetylcholinesterase.

Alzheimer's disease is one of the causes associated with the early stages of dementia. Nowadays, the main treatment available is to inhibit the actions of the acetylcholinesterase (AChE) enzyme, which has been identified as responsible for the disease. In this study, computational methods were used to examine the structure and therapeutic ability of chemical compounds extracted from Millettia brandisiana natural products against AChE. This plant is commonly known as a traditional medicine in Vietnam and Thailand for the treatment of several diseases. Furthermore, machine learning helped us narrow down the choice of 85 substances for further studies by molecular docking and molecular dynamics simulations to gain deeper insights into the interactions between inhibitors and disease proteins. Of the five top-choice substances, γ-dimethylallyloxy-5,7,2,5-tetramethoxyisoflavone emerges as a promising substance due to its large free binding energy to AChE and the high thermodynamic stability of the resulting complex.

A computational approach to identify phytochemicals as potential inhibitor of acetylcholinesterase: Molecular docking, ADME profiling and molecular dynamics simulations.

Inhibition of acetylcholinesterase (AChE) is a crucial target in the treatment of Alzheimer's disease (AD). Common anti-acetylcholinesterase drugs such as Galantamine, Rivastigmine, Donepezil, and Tacrine have significant inhibition potential. Due to side effects and safety concerns, we aimed to investigate a wide range of phytochemicals and structural analogues of these compounds. Compounds similar to the established drugs, and phytochemicals were investigated as potential inhibitors for AChE in treating AD. A total of 2,270 compound libraries were generated for further analysis. Initial virtual screening was performed using Pyrx software, resulting in 638 molecules showing higher binding affinities compared to positive controls Tacrine (-9.0 kcal/mol), Donepezil (-7.3 kcal/mol), Galantamine (-8.3 kcal/mol), and Rivastigmine (-6.4 kcal/mol). Subsequently, ADME properties were assessed, including blood-brain barrier permeability and Lipinski's rule of five violations, leading to 88 compounds passing the ADME analysis. Among the rivastigmine analogous, [3-(1-methylpiperidin-2-yl)phenyl] N,N-diethylcarbamate showed interaction with Tyr123, Tyr336, Tyr340, Phe337, Trp285 residues of AChE. Tacrine similar compounds, such as 4-amino-2-styrylquinoline, exhibited bindings with Tyr123, Phe337, Tyr336, Trp285, Trp85, Gly119, and Gly120 residues. A phytocompound (bisdemethoxycurcumin) showed interaction with Trp285, Tyr340, Trp85, Tyr71, and His446 residues of AChE with favourable binding. These findings underscore the potential of these compounds as novel inhibitors of AChE, offering insights into alternative therapeutic avenues for AD. A 100ns simulation analysis confirmed the stability of protein-ligand complex based on the RMSD, RMSF, ligand properties, PCA, DCCM and MMGBS parameters. The investigation suggested 3 ligands as a potent inhibitor of AChE which are [3-(1-methylpiperidin-2-yl)phenyl] N,N-diethylcarbamate, 4-Amino-2-styrylquinoline and bisdemethoxycurcumin. Furthermore, investigation, including in-vitro and in-vivo studies, is needed to validate the efficacy, safety profiles, and therapeutic potential of these compounds for AD treatment.

In Vitro and Molecular Docking Evaluation of the Anticholinesterase and Antidiabetic Effects of Compounds from Terminalia macroptera Guill. & Perr. (Combretaceae).

Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant Terminalia macroptera and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From 1H and 13C NMR data, the compounds were identified as 3,3'-di-O-methyl ellagic acid (1), 3,3',4'-tri-O-methyl ellagic acid-4-O-ß-D-xylopyranoside (2), 3,3',4'-tri-O-methyl ellagic acid-4-O-ß-D-glucopyranoside (3), 3,3'-di-O-methyl ellagic acid-4-O-ß-D-glucopyranoside (4), myricetin-3-O-rhamnoside (5), shikimic acid (6), arjungenin (7), terminolic acid (8), 24-deoxysericoside (9), arjunglucoside I (10), and chebuloside II (11). The derivatives of ellagic acid (1-4) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3'-di-O-methyl ellagic acid, with IC50 values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (1-5). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC50 value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC50 value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3'-di-O-methyl ellagic acid (IC50 = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC50 = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC50 = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for 1-11 reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of -4.03 to -10.20 kcalmol-1. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable.

Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents.

Alzheimer's disease (AD), a severe neurodegenerative disorder, imposes socioeconomic burdens and necessitates innovative therapeutic strategies. Current therapeutic interventions are limited and underscore the need for novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes implicated in the pathogenesis of AD. In this study, we report a novel synthetic strategy for the generation of 2-aminopyridine derivatives via a two-component reaction converging aryl vinamidinium salts with 1,1-enediamines (EDAMs) in a dimethyl sulfoxide (DMSO) solvent system, catalyzed by triethylamine (Et3N). The protocol introduces a rapid, efficient, and scalable synthetic pathway, achieving good to excellent yields while maintaining simplistic workup procedures. Seventeen derivatives were synthesized and subsequently screened for their inhibitory activity against AChE and BChE. The most potent derivative, 3m, exhibited an IC50 value of 34.81 ± 3.71 µM against AChE and 20.66 ± 1.01 µM against BChE compared to positive control donepezil with an IC50 value of 0.079 ± 0.05 µM against AChE and 10.6 ± 2.1 µM against BChE. Also, detailed kinetic studies were undertaken to elucidate their modes of enzymatic inhibition of the most potent compounds against both AChE and BChE. The promising compound was then subjected to molecular docking and dynamics simulations, revealing significant binding affinities and favorable interaction profiles against AChE and BChE. The in silico ADMET assessments further determined the drug-like properties of 3m, suggesting it as a promising candidate for further pre-clinical development.

Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases.

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment.

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and ß-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aß aggregation inhibition in a self- and AChE-induced Aß aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aß-induced cognitive deficits in the Aß-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aß and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.

Characterization of Phenolic Compounds in Extra Virgin Olive Oil from Granada (Spain) and Evaluation of Its Neuroprotective Action.

The olive oil sector is a fundamental food in the Mediterranean diet. It has been demonstrated that the consumption of extra virgin olive oil (EVOO) with a high content of phenolic compounds is beneficial in the prevention and/or treatment of many diseases. The main objective of this work was to study the relationship between the content of phenolic compounds and the in vitro neuroprotective and anti-inflammatory activity of EVOOs from two PDOs in the province of Granada. To this purpose, the amounts of phenolic compounds were determined by liquid chromatography coupled to mass spectrometry (HPLC-MS) and the inhibitory activity of acetylcholinesterase (AChE) and cyclooxygenase-2 (COX-2) enzymes by spectrophotometric and fluorimetric assays. The main families identified were phenolic alcohols, secoiridoids, lignans, flavonoids, and phenolic acids. The EVOO samples with the highest total concentration of compounds and the highest inhibitory activity belonged to the Picual and Manzanillo varieties. Statistical analysis showed a positive correlation between identified compounds and AChE and COX-2 inhibitory activity, except for lignans. These results confirm EVOO's compounds possess neuroprotective potential.

The Cholinergic Selectivity of FDA-Approved and Metabolite Compounds Examined with Molecular-Docking-Based Virtual Screening.

The search for selective anticholinergic agents stems from varying cholinesterase levels as Alzheimer's Disease progresses from the mid to late stage. In this computational study, we probed the selectivity of FDA-approved and metabolite compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with molecular-docking-based virtual screening. The results were evaluated using locally developed codes for the statistical methods. The docking-predicted selectivity for AChE and BChE was predominantly the consequence of differences in the volume of the active site and the narrower entrance to the bottom of the active site gorge of AChE.

Anti-Diabetic, Anti-Cholinesterase, and Anti-Inflammatory Potential of Plant Derived Extracts and Column Semi-Purified Fractions of Ficus benghalensis.

BACKGROUND: The present study aimed to investigate the in-vitro anti-diabetic, anti-cholinesterase, and anti-inflammatory potential of extracts from different parts of Ficus benghalensis, including leaves, stem, and roots, as well as isolated column fractions (F-B-1 C, F-B-2 C, F-B-3 C, and F-B-4 C). METHODS: The extracts and subsequent fractions were evaluated for their inhibitory activity against key enzymes involved in diabetes [α-glucosidase and α-amylase], neurodegenerative diseases [acetylcholinesterase and butyrylcholinesterase], and inflammation (cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX)). RESULTS: The results showed that F. benghalensis leaf extract exhibited the highest α-glucosidase inhibitory activity (73.84%) and α-amylase inhibitory activity (76.29%) at 1000 µg/mL. The stem extract (65.50%) and F-B-2 C fraction (69.67%) also demonstrated significant α-glucosidase inhibitory activity. In terms of anti-cholinesterase activity, the extracts of roots, leaves, and stem showed promising inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with half maximal inhibitory concentration (IC50) values ranging from 50.50 to 474.83 µg/mL. The derived fractions (F-B-1 C, F-B-2 C, F-B-3 C, and F-B-4 C) also exhibited notable inhibition of AChE and BChE, with IC50 values from 91.85 to 337.94 µg/mL. Moreover, the F-B-3 C fraction demonstrated the highest COX-2 inhibitory potential (85.72%), followed by F-B-1 C (83.13%), the stem extract (80.85%), and the leaves extract (79.00%). The F-B-1 C fraction showed the highest 5-LOX inhibitory activity (87.63%), while the root extract exhibited the lowest inhibition (73.39%). CONCLUSIONS: The results demonstrated promising bioactivity, suggesting the potential of F. benghalensis as a source of natural compounds with therapeutic applications. Further studies are required to identify and isolate the active components responsible for these effects and to evaluate their in-vivo efficacy and safety.

Bioactive Alkaloids from the Mangrove-Derived Fungus Nigrospora oryzae SYSU-MS0024.

Chemical investigation of marine fungus Nigrospora oryzae SYSU-MS0024 cultured on solid-rice medium led to the isolation of three new alkaloids, including a pair of epimers, nigrosporines A (1) and B (2), and a pair of enantiomers, (+)-nigrosporine C (+)-3, and (-)-nigrosporine C (-)-3, together with eight known compounds (4-11). Their structures were elucidated based on extensive mass spectrometry (MS) and 1D/2D nuclear magnetic resonance (NMR) spectroscopic analyses and compared with data in the literature. The absolute configurations of compounds 1-3 were determined by a combination of electronic circular dichroism (ECD) calculations, Mosher's method, and X-ray single-crystal diffraction technique using Cu Kα radiation. In bioassays, compound 2 exhibited moderate inhibition on NO accumulation induced by lipopolysaccharide (LPS) on BV-2 cells in a dose-dependent manner at 20, 50, and 100 µmol/L and without cytotoxicity in a concentration of 100.0 µmol/L. Moreover, compound 2 also showed moderate acetylcholinesterase (AChE) inhibitory activities with IC50 values of 103.7 µmol/L. Compound 5 exhibited moderate antioxidant activity with EC50 values of 167.0 µmol/L.

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases.

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10-30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

Lycopodium alkaloids from Huperzia serrata and their cholinesterase inhibitory activities.

Huperzia serrata, belonging to the Lycopodiaceae family, has been traditionally utilized for the management of treating rheumatic numbness, arthritic pain, dysmenorrhea, and contusions. This plant is a rich source of lycopodium alkaloids, some of which have demonstrated notable cholinesterase inhibitory activity. The objective of this study was to identify lycopodium alkaloids with cholinesterase inhibitory properties from H. serrata. The structures of these alkaloids were elucidated by HRESIMS, NMR (including a 1H-15N HMBC experiment), ECD methods and single-crystal X-ray diffraction. The inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were assessed using a modified Ellman's method. Consequently, sixteen lycopodium alkaloids (1-16), including ten previously undescribed ones named huperradines A-G and huperradines I-K (1-7 and 9-11), along with one previously undescribed naturally occurring compound, huperradine H (8), were isolated from H. serrata. Among these, compounds 7 and 1 exhibited potent and moderate AChE inhibition, with IC50 values of 0.876 ± 0.039 µM and 13.125 ± 0.521 µM, respectively. Our results suggest that huperradine G (7) may be a promising lead compound for the development of new AChE inhibitors for Alzheimer's disease.

Advances in the Synthesis of Biologically Active Quaternary Ammonium Compounds.

This review provides a comprehensive overview of recent advancements in the design and synthesis of biologically active quaternary ammonium compounds (QACs). The covered scope extends beyond commonly reviewed antimicrobial derivatives to include synthetic agents with antifungal, anticancer, and antiviral properties. Additionally, this review highlights examples of quaternary ammonium compounds exhibiting activity against protozoa and herbicidal effects, as well as analgesic and anesthetic derivatives. The article also embraces the quaternary-ammonium-containing cholinesterase inhibitors and muscle relaxants. QACs, marked by their inherent permanent charge, also find widespread usage across diverse domains such as fabric softeners, hair conditioners, detergents, and disinfectants. The effectiveness of QACs hinges greatly on finding the right equilibrium between hydrophilicity and lipophilicity. The ideal length of the alkyl chain varies according to the unique structure of each QAC and its biological settings. It is expected that this review will provide comprehensive data for medicinal and industrial chemists to design and develop novel QAC-based products.

Synthesis of new N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives and evaluation of their AChE, BChE, and BACE-1 inhibitory activities.

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.

Preferential Door for Ligand Binding and Unbinding Pathways in Inhibited Human Acetylcholinesterase.

Rising global population and increased food demands have resulted in the increased use of organophosphate pesticides (OPs), leading to toxin accumulation and transmission to humans. Pralidoxime (2-PAM), an FDA-approved drug, serves as an antidote for OP therapy. However, the atomic-level detoxification mechanisms regarding the design of novel antidotes remain unclear. This is the first study to examine the binding and unbinding pathways of 2-PAM to human acetylcholinesterase (HuAChE) through three identified doors using an enhanced sampling method called ligand-binding parallel cascade selection molecular dynamics (LB-PaCS-MD). Remarkably, LB-PaCS-MD could identify a predominant in-line binding mechanism through the acyl door at 63.79% ± 6.83%, also implicating it in a potential unbinding route (90.14% ± 4.22%). Interestingly, crucial conformational shifts in key residues, W86, Y341, and Y449, and the Ω loop significantly affect door dynamics and ligand binding modes. The LB-PaCS-MD technique can study ligand-binding pathways, thereby contributing to the design of antidotes and covalent drugs.

Potential antioxidant, α-glucosidase, butyrylcholinesterase and acetylcholinesterase inhibitory activities of major constituents isolated from Alpinia officinarum hance rhizomes: computational studies and in vitro validation.

Alpinia officinarum is a commonly used spice with proven folk uses in various traditional medicines. In the current study, six compounds were isolated from its rhizomes, compounds 1-3 were identified as diarylheptanoids, while 4-6 were identified as flavonoids and phenolic acids. The isolated compounds were subjected to virtual screening against α-glucosidase, butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) enzymes to evaluate their potential antidiabetic and anti-Alzheimer's activities. Molecular docking and dynamics studies revealed that 3 exhibited a strong binding affinity to human a α- glucosidase crystal structure compared to acarbose. Furthermore, 2 and 5 demonstrated high potency against AChE. The virtual screening results were further supported by in vitro assays, which assessed the compounds' effects on α-glucosidase, cholinesterases, and their antioxidant activities. 5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenylheptan-3-one (2) showed potent antioxidant effect in both ABTs and ORAC assays, while p-hydroxy cinnamic acid (6) was the most potent in the ORAC assay. In contrary, kaempferide (4) and galangin (5) showed the most potent effect in metal chelation assay. 5-Hydroxy-1,7-diphenylhepta-4,6-dien-3-one (3) and 6 revealed the most potent effect as α-glucosidase inhibitors where compound 3 showed more potent effect compared to acarbose. Galangin (5) revealed a higher selectivity to BChE, while 2 showed the most potent activity to (AChE).