Against Acetylcholinesterase Research Articles

Anti-cholinesterase profile of Murraya koenigii (L.) Spreng essential oil and its chemical constituents

Traditionally, Murraya koenigii (L.) Spreng has been used as an ingredient in medicinal formulations. Several studies have reported on the potential of M. koenigii leaves to enhance learning and memory functions in animal models. This study aimed to identify the chemical constituents and evaluate the anti-cholinesterase activity of the essential oil extracted from M. koenigii leaves. The essential oil extracted via hydrodistillation was analyzed using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). A total of 41 constituents were identified, with β-phellandrene (35.42%), β-caryophyllene (16.79%) and α-pinene (17.75%) predominating in the essential oil. Using Ellman’s colorimetric method, the M. koenigii essential oil demonstrated potent inhibitory activity against acetylcholinesterase (AChE), with an IC50 value of 36.89 μg/mL. Interestingly, a mixture of the three major constituents (β-phellandrene, β-caryophyllene, and α-pinene) was more effective than the individual constituents (β-caryophyllene and α-pinene). In conclusion, the study on the neuroprotective effects of M. koenigii essential oil has yielded promising results.

Comparison of Essential Oils of Schinus molle L. Leaves Growing in Different Regions of Algeria in Terms of Their Chemical Compositions and Various Biological Activities

ABSTRACTThis preliminary study investigated the chemical composition and biological properties of essential oils derived from Schinus molle L. leaves obtained from three specific regions in Algeria: Algiers (SMA), Djelfa (SMD), and Mascara (SMM). Gas chromatography (GC) and Gas chromatography–Mass Spectrometry (GC–MS) analyses confirmed the presence of 52 compounds (100.0%) in SMA essential oil, 50 compounds (100.0%) in SMD, and 72 compounds (100.0%) in SMM essential oils. The main components of SMA oil were camphene (31.82%), limonene (14.71%), and p‐cymene (9.25%). In SMD and SMM oils, α‐phellandrene (14.25% and 12.70%), limonene (13.02% and 11.90%), and germacrene D (10.62% and 10.15%) were the major components, respectively. The antioxidant characteristics were evaluated using five methods: β‐carotene‐linoleic acid, DPPH, ABTS+, CUPRAC, and Metal chelating assays. The results revealed a moderate to low anti‐oxidant effect, with SMA essential oils exhibiting the highest activity. A moderate inhibitory effect against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α‐glucosidase, α‐amylase, urease, and tyrosinase was observed, indicating anti‐enzymatic activity. Nevertheless, all samples had higher IC50 values for both antioxidant and anti‐enzymatic activities than 200 μg/mL. It was determined that regional differences in the locations where S. molle grows showed both qualitative and quantitative differences in essential oil components. This difference was also detected in the biological activities of the essential oils. The anti‐inflammatory capacities of the three samples were assessed using Human Red Blood Cell (HRBC) membrane stabilisation and egg albumin denaturation techniques. The results showed effective anti‐inflammatory activity in all three samples. The antimicrobial efficacy was evaluated using a range of tests, such as anti‐quorum sensing, violacein inhibition, anti‐swimming, and anti‐swarming assays, demonstrating moderate activity. No toxic effects were observed at the tested dosages when assessing cytotoxicity against a healthy cell line (CCD18‐Co). This thorough examination provides valuable insights into the chemical composition and bioactive properties of essential oils derived from S. molle. These findings indicate the possible use of these essential oils in the food, medicinal, and cosmetic industries.

Synthesis, biological evaluation, molecular docking and dynamic simulation of novel benzofuran derivatives as potential agents against Alzheimer's disease

We have synthesized novel benzofuran derivatives (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives showed inhibitory activities having IC50 values ranging from 0.70 ± 0.01 to 28.10 ± 0.50 µM (against AChE), while 0.80 ± 0.01 to 31.20 ± 0.60 µM (against BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 and 4.50 ± 0.10 µM, respectively). Except derivative 5, all other derivatives of the series showed good inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, but some analogues like 2, 4, 7, 14, 15, and 16 displayed many folds better inhibitory activity than the standard drug donepezil. The influences of substituents on inhibitory activity were superficially resonated via the structure-activity relationship. We established molecular docking and MD simulation studies to confirm the binding interaction between potent derivatives and active sites of enzymes.

Exploring of Chemical Profile and Biological Activities of Three Ocimum Species From Comoros Islands: A Combination of In Vitro and In Silico Insights.

Ocimum species have a great interest in different traditional medicinal systems. This study examined the chemical composition, antioxidant properties, enzyme inhibitory effects, and antibacterial and antifungal activities of the aerial parts of Ocimum gratissimum, Ocimum americanum, and Ocimum basilicum from the Comoros Islands. The extracts were analyzed using high-performance liquid chromatography-mass spectrometry (HPLC-MS) to determine their chemical composition. Antioxidant activity was assessed using 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), chelating ability, and phosphomolybdenum radical scavenging assays. Enzyme inhibitory activities against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, amylase, and glucosidase were evaluated using spectrophotometric methods. Antibacterial and antifungal activities were tested using the broth microdilution method against selected pathogenic microorganisms. The selected enzymes and proteins were evaluated using in silico methods with biomolecules from these plants. In addition, 111 different metabolites were identified in the tested extracts using advanced HPLC/MS techniques. The most significant number of detected compounds were derivatives of hydroxycinnamic acids, followed by flavonoid glycosides and aglycones and derivatives of hydroxybenzoic acids. All three Ocimum species exhibited significant antioxidant activities, O. gratissimum exhibited the best-reducing abilities in CUPRAC and FRAP assays. In addition, enzyme inhibitory assays revealed that O. americanum had the most potent inhibitory effect on tyrosinase (48.01 ± 3.89 mg kojic acid equivalent [KAE]/g), and amylase (1.08 ± 0.02 mmol acarbose equivalent [ACAE]/g). Antibacterial and antifungal tests demonstrated that the extracts possess broad-spectrum activity. Molecular docking results showed that compounds exhibited remarkable binding energies with target enzymes and proteins. The molecular dynamics simulations identified chicoric acid with MurE of Staphylococcus aureus complex as the most promising drug candidate. These findings support their traditional medical and nutraceutical uses and suggest possibilities for natural functional applications.

Synthesis and biological studies of acetophenone-based novel chalcone, semicarbazone, thiosemicarbazone and indolone derivatives: Structure-Activity relationship, molecular docking, molecular dynamics, and kinetic studies

This study presents the synthesis and evaluation of nine acetophenone derivatives (1–9), with compounds 2, 4, 5, 6, 7, and 9 being novel and synthesized for the first time. These derivatives encompass diverse structural motifs including chalcone, thiosemicarbazone, semicarbazone, and indolone derivatives. The structures of synthesized compound were confirmed by NMR analysis. The synthesized compounds were assessed for their in vitro enzyme inhibition against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-Glycosidase enzymes, as well as their antioxidant capacities using the DPPH radical scavenging assay. With Ki values ranging from 8.96±0.40 to 44.16±4.25 nM, these showed effective inhibition of AChE. However, the inhibitory characteristics of all drugs were almost the same. The Ki values of the two most active compounds, (3) and (4), were 8.96±0.40 and 11.33±0.58 nM, respectively. Regarding α-Glycosidase, they demonstrate that all novel compounds (1–9) have IC50 values between 30.16 and 133.98 µM, whereas the Ki values vary from 42.71±5.90 to 128.78±8.03 µM. Compound 4 emerged as a notable inhibitor, displaying significant inhibition against all used enzymes. Molecular docking studies revealed its exceptional binding affinities, corroborated by MM-GBSA ΔG binding free energies, and Glide Emodel scores. Compound 7 also exhibited promising inhibitory potential against α-Glycosidase. Docking scores for hAChE -12.207, for hBChE -10.140 and for α-Glycosidase -10.590 kcal/mol. The 250 ns molecular dynamics simulations confirmed the stability of the ligand-protein complexes, particularly with compound 4. The ligand-protein complexes were found extremely stable according to the MD simulations. Additionally, ADME predictions indicated favorable pharmacokinetic properties and drug-likeness for all compounds, further supporting their potential as orally active agents. Compound 4, in particular, stands out as a multitarget drug candidate, with strong inhibition against key enzymes implicated in neurodegenerative diseases and diabetes, suggesting its therapeutic potential in these conditions.

Chemical profiling By LC[sbnd]HRMS, antioxidant potential, enzyme inhibition, molecular docking and molecular dynamics simulations of Acantholimon acerosum

The principal objective of this study is to evaluate phenolic content and biological activity in vitro and silico properties of A. acerosum (Willd.) Boiss. subsp. acerosum's (A. acerosum). The antioxidant activity of A. acerosum was assessed in a variety of bioanalytical methods. Strong antioxidant activity was shown for both water (WEAA) and ethanol (EEAA) extracts of the aerial parts of A. Acerosum. Also, it was shown that hyperoside is the most prevalent phenolic compound in EEAA (12,940.83 mg kg−1) and WEAA (5409.67 mg kg−1) by LCHRMS. The enzyme inhibitory abilities of the EEAA were then realised. The IC50 values of EEAA against acetylcholinesterase (AChE) (E.C.3.1.1.7), α-glycosidase (E.C.3.2.1.20), and α-amylase (E.C.3.2.1.1) were determined as 1.828 μg mL−1, 0.615 μg mL−1, and 1.081 μg mL−1, respectively. Subsequently, the α-amylase, α-glycosidase, and AChE enzymes were subjected to molecular docking and molecular dynamic interactions using major compounds of EEAA as ligands. High enzyme-inhibiting properties of EEAA were also determined in silico. It has been reported that numerous traditional and contemporary medical applications of A. acerosum. It can be said that the effective antioxidant results obtained in our study are the basis of previously performed traditional or contemporary medical practices.

Synthesis, biological and computational evaluation of benzoxazole hybrid analogs as potential anti-Alzheimer's agents.

Aim: Current study aims exploration of bis-benzoxazole bearing bis-Schiff base scaffolds (1-16) as anti-Alzheimer's agents.Materials & methods: 2-aminophenol is used as starting materials which react with different reagents in different step to give us bis-benzoxazole bearing bis-Schiff base analogs. NMR and HREI-MS techniques were used for characterization. All derivatives demonstrated varied range of activities with IC50 values 1.10±0.40-24.50±0.90μM against acetylcholinesterase (AChE) and 1.90±0.70-28.60±0.60μM against butyrylcholinesterase (BuChE) in contrast to donepezil. In both cases, analog-3 was found most potent. Molecular docking explored modes of interactions between scaffolds and receptor sites of targeted enzymes.Conclusion: This study offering promising approach for optimization and development of potent inhibitors of cholinesterase enzymes.

A multifunctional natural treasure based on a “one stone, many birds” strategy for designing health-promoting applications: Tordyliumapulum

Wild plants provide important bioactive compounds, and their analysis relies heavily on selecting the right extraction techniques and solvents. This study was conducted to determine the phenolic content and biopharmaceutical potential of four different extracts (ethyl acetate, ethanol, 70% ethanol, and water) from the aerial parts of wild plant Tordylium apulum L. The biochemical profile of the extract was screened using high performance liquid chromatography -mass spectrometry (HPLC-MS) analysis. The total phenolic and flavonoid content was examined using the Folin-Ciocalteu assay and the aluminium trichloride assay, respectively. The antioxidant activity was evaluated through several tests, including 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), phosphomolybdenum (PBD), and metal chelating activity (MCA). Five types of enzyme inhibition activity were tested against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase. Additionally, For the first time, the inhibitory activity of T. apulum extract against human carbonic anhydrase isoenzymes I and II (hCA-I and hCA-II) was evaluated. Fifty-five compounds for negative ionization mode, and twenty-eight compounds for positive ionization mode were recorded in HPLC-MS analysis and they were polyphenolic, flavonoids, carbohydrates, sugar alcohol and amino acids. These results indicate that different solvents extract varying levels of antioxidants from T. apulum, with ethanol and water extracts generally exhibiting superior antioxidant activities. The ethanol extract of T. apulum exhibited the maximum contents of total phenolics measuring 33.71 mg gallic acid equivalent (GAE)/g. The ethanol extract exhibited the highest inhibition of AChE with 2.28 mg galanthamine equivalent (GALAE)/g. The ethyl acetate and ethanol extracts also showed the highest hCA-I and hCA-II inhibition potential, respectively. The ethanol-water and water extracts acted on the biofilm of E. coli (49.93% and 45.22%, respectively), and the biofilm of P. aeruginosa (50.68% and 44.46%, respectively). The extracts were tested on different cell lines for cytotoxic potentials and in particular the water extract induced the apoptotic pathways in cervical cancer (HELA) cell lines. In conclusion, T. apulum exhibit multidirectional biological properties and it could be considered as a versatile agent for the development of health-promoting applications.

Biological study with molecular mechanism of imidazothiazole based Schiff bases as anti-Alzheimer agent: Insight into the role of synthesis, molecular docking and ADMET analysis

The current study aims to develop synthetic route and biological evaluation regarding a series of fused imidazothiazole derived Schiff base hybrid derivatives (1–17), synthesized by treating imidazothiazole bearing ester with hydrazine. The first intermediate imidazothiazole bearing hydrazide upon treating with ammonium thiocyanate was cyclized in the presence of 1,2-dioxane and potassium carbonate to second intermediate fused imidazothiazole bearing 2-aminothiadiazole. This intermediate was then mixed substituted benzaldehyde to afford fused imidazothiazole derived Schiff base hybrid derivatives. The current study revealed that the synthesized derivatives were examined and found with high inhibition profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in-comparison with marketed drug donepezil (IC50=7.20 ± 0.10 and 7.80 ± 0.20 µM for AChE and BuChE). Among all the derivatives, analog 11 (IC50=2.10 ± 0.30 and 2.80 ± 0.20 µM) was the one having highest inhibitory profile against both enzymes due to attachment of highly active tri-fluoromethyl group and hence regarded as potent analog. Furthermore, analog 7, 8, 9, 12 and 14 were also studied to exhibit excellent activity due to the attachment of electron donating groups and were found modest in contrast with the standard marketed drug. Protein-ligand interactions were observed through in-silico docking studies and their drug likeness properties were studied through ADMET analysis.

Synthesis, characterization of novel mannich bases and their acetylcholinesterase and glutathione S-transferase inhibitory properties: An in vitro and in silico mechanism research

In this study, 4-((3,4-Dimethoxybenzylidene)amino)-5-alkyl(aryl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a-g) reacted with formaldehyde and 2,6-dimethylmorpholine to obtain seven novel potential biologically active 4-((3,4-Dimethoxybenzylidene)amino)-2-((2,6-dimethylmorpholino)methyl)-5-alkyl(aryl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a-g). The structures (5a-g) of newly synthesized compounds were characterized using FT-IR, 1H-NMR, and 13C-NMR spectral data. The synthesized compounds (5a-g) were investigated for it is in vitro enzyme inhibition properties. Results demonstrated that the newly synthesized compounds had valuable enzyme inhibition activities against acetylcholinesterase (AChE) and glutathione S-transferase (GST) enzymes. Their Ki values were calculated in the range of 0.96 ± 0.0557- 9.7967 ± 5.3105 µM, while their IC50 values were calculated in the range of 1.333–3.551 µM. Tacrine was used for AChE, Ethacrynic acid was used for GST as positive standard. Molecular docking studies revealed that compound 5b binds to AChE and compound 5f binds to GST with high affinity (−10.2 and −9.1 kcal/mol) in protein-ligand complexes. The stability of the ligand-protein complexes was confirmed by 100 ns molecular dynamics simulations.

Design and synthesis of novel tetrahydronephthalene-1-amine based analogues as cholinesterase inhibitors

Inhibiting cholinesterase (ChE) such as AChE and BChE is thought to be one of the most effective treatments for Alzheimer’s disease (AD) and dementia. In the present work, a new facile method for (1S,4S)-4-(3,4-dichlorophenyl)-n-methyl-1,2,3,4-tetrahydronaphthalen-1-amine based analogues 4 (a–p) in good yield (66–93 %) were synthesized by refluxing demethylsertraline (2) with different aldehydes and ketones 3 (a–p). The newly synthesized analogues 4 (a–p) were characterized by physical and spectroscopic techniques for instance FTIR, LR-MS and HR-MS. The synthesized demethylsertraline based analogues 4 (a–p) were examined for their biological activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In case of AChE activity, electron donating substituents have shown more inhibition as 4–hydroxyphenyl– (4b, IC50, 0.98 ± 0.99 µM) and 3,4–dimethoxyyphenyl– (4c, IC50, 1.0 ± 0.98 µM) and exhibited excellent binding affinity. In case of BChE activity, 4e consisting of electron withdrawing substituent has shown potent inhibition (1.26 ± 0.34 µM). Similarly, 4i and 4n depicted good inhibition with IC50 values 1.66 ± 0.78 µM and 1.66 ± 0.98 µM respectively as they possess weakly donating substituents. The structure activity relationship of BChE inhibition has shown opposite trend than AChE inhibition. It has been scrutinized that strong electron donating substituent decrease the BChE inhibitory activities whereas electron withdrawing groups greatly enhance the enzyme inhibition activity. In silico study of the synthesized compounds 4 (a–p) of the series was carried out. Compound 4b demonstrated excellent interaction with AChE compare with Eserine (standard) with a score of 6228 and an ACE value of –101.33 kcal/mol. Compound 4e demonstrated potent interaction with BChE compare with Eserine (standard) with a score of 6028 and ACE value of –258.53 kcal/mol. Compound 4b has the potential to serve as a lead molecule in medication development for Alzheimer’s disease treatment.

A novel class of thiazole based thiadiazole hybrids: The privileged scaffolds of potent anti-Alzheimer's activity along with molecular docking and ADME analysis

A novel series of thiazole-thiadiazole based schiff base derivatives (1–16) were synthesized and examined for their inhibitory profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). All the compounds exhibited excellent inhibitory activity ranging from IC50= 1.87 ± 1.47 to 27.4 ± 2.45 µM for AChE and 1.72 ± 1.43 to 29.4 ± 1.87 µM for BuChE when compared with the standard drug donepezil (IC50= 3.87 ± 1.14 µM and 3.56 ± 2.52 µM for AChE and BuChE, respectively). Among the members of the whole series, compounds-6 (IC50 = 3.49 ± 1.20 µM, 3.18 ± 0.27 µM), 7 (IC50 = 3.20 ± 1.14 µM, 3.21 ± 0.49 µM), 8 (IC50 =1.87 ± 1.47 µM, IC50 = 1.72 ± 1.43) and 9 (IC50 = 2.18 ± 1.02 µM, IC50 = 2.02 ± 0.49 µM), showed remarkable potency against AChE and BuChE and emerged as anti-alzheimer's agents. Molecular docking study revealed the excellent binding interactions of ligands with different amino acids of the target enzymes. Structure activity relationship (SAR) study was also conducted to evaluate inhibitory potency of all the derivatives that depends on the position, number and nature of the substituents. Furthermore, ADME outcomes authenticate the drug likeness of the potent analogs. Structural confirmation of the derivatives was achieved through different spectroscopic techniques, including 13C NMR, 1H NMR and HREI-MS.

Phenyldiazenyl-phenoxy-1,2,3-triazol-acetamide derivatives as new dual cholinesterase Inhibitors: Design, synthesis, in vitro, and in silico enzymatic inhibition evaluations

In this work, phenyldiazenyl-phenoxy-1,2,3-triazol-acetamide as new scaffold was designed by molecular hybridization of the active pharmacophores in the cholinesterase inhibitors. Twelve derivatives 7a-l of the title scaffold were synthesized in high yields using simple and efficient chemical reactions. The inhibitory activities of all the title compounds 7a-l were investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as two important enzymatic targets in Alzheimer's disease (AD). The obtained in vitro data showed that all new compounds were more potent than positive control galantamine against both studied enzymes. Representatively, the most potent compound against AChE (compound 7 g) was 2.7-times and the most potent compound against BChE (compound 7k) was 40.5-times more potent than galantamine. Docking study demonstrated that the most potent compounds interacted with main components of the active sites of AChE and BChE. Molecular dynamics of the most potent compounds showed that these compounds formed stable complex with target enzymes AChE and BChE. The most potent compounds also had acceptable pharmacokinetic properties as oral agents.

Quercetagetin 3,7 dimethyl ether polymorphs as multi-targeted anti-amyloid agents: Target to cognitive impairment in Alzheimer's disease

The extraction of biologically active natural products from plants and the assessment of their medicinal properties play a crucial role in drug development. Taking that into consideration, the current research work was designed. Bioassay-guided isolation from Parthenium hysterophorus led to the isolation of two antioxidant compounds: polymorphs A (1) and B (2) of Quercetagetin 3,7-dimethyl ether which demonstrated IC50 values 13.00 ± 0.63 μM and 16.56 ± 0.82 μM, respectively in the DPPH assay. These polymorphs were further evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In silico studies, including molecular docking, and molecular dynamic simulations were conducted using β-secretase, γ-secretase, AChE, and BChE enzymes. Interestingly, compound 1 demonstrated excellent antioxidant activity and showed the better binding affinities -9.0 kcal/mol (BChE), −8.5 kcal/mol (β-secretase), -8.2 kcal/mol (γ-secretase) and -7.7 kcal/mol (AChE) as compared to compound 2. Due to these promising results, compound 1 was selected for molecular dynamic simulations to further evaluate the stability and flexibility of its complexes. Overall, both in silico and in vitro results confirmed that compound 1 and compound 2 exhibit distinct behavior, making them promising candidates as antioxidants and inhibitors of AChE, BChE, and secretases, potentially targeting cognitive impairment in Alzheimer's disease (AD).

Preparation of Polyphenol-Rich Herbal Beverages from White Willow (Salix alba) Bark with Potential Alzheimer’s Disease Inhibitory Activity In Silico

White willow (Salix alba) is a medicinal plant traditionally used to treat pain and inflammation. The aims of this study were to produce polyphenol-rich herbal beverages from willow bark with different ethanol content, temperatures, and solvent pH and to explore neuroprotective potentials of willow polyphenols. The phenolic compounds quantified in the willow infusions were salicin, chlorogenic acid, epicatechin, p-salicylic acid, and p-coumaric acid; the former three compounds exhibited promising inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in molecular docking studies. Total phenol content and antioxidant activity were maximum when prepared with 50% ethanol-in-water at room temperature. Although aqueous infusions contained fewer total phenols than those extracted with 50% hydroalcoholic solutions, they enhanced the extraction of chlorogenic acid and salicin content, which may possess promising neuroprotective potentials. The addition of citric acids in hot water infusions led to a higher proportion of non-tannins and had a lighter appearance, which may result in less astringent mouthfeel and better consumer acceptance. Overall, the obtained results indicate that willow bark prepared with hot water and/or with addition of citric acids is rich in bioactive compounds with high antioxidant activity and possible neuroprotective activities in silico, which could serve as valuable ingredients for inclusion in functional beverages.

Advances in Cholinesterase Inhibitor Research-An Overview of Preclinical Studies of Selected Organoruthenium(II) Complexes.

Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer's disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.

UPLC-MS/MS-based metabolomics and chemometrics unveil metabolic patterns and their regulatory pathways over the course of pumpkin seeds (Cucurbita maxima) germination

While pumpkin seeds (Cucurbita maxima) are regarded as agro-industrial waste, they serve as powerhouses packed with a plethora of valuable compounds with potential nutraceutical significance. The present work offers an integrated view of metabolites dynamics and their regulatory pathways over the course of pumpkin seeds germination and their potential entanglements on Alzheimerʼs disease (AD) mitigation through Ultra Performance Liquid Chromatography-mass spectrometry (UPLC-MS/MS) analysis and chemometrics. A total of 76 compounds spanning amino acids, phenolic acid, flavonoids, lignans, vitamins, fatty acids, phospholipids and phytosterols were annotated revealing changing trends during germination process. Coincidentally, orthogonal projection to latent structures-discriminant analysis (OPLS-DA) demonstrated a clear separation trend among the five pumpkin samples assuring their chemical heterogeneity. Complementarily, OPLS-DA models were constructed in different timepoint comparisons to pick out the significant metabolic features which were subsequently imported into MetaboAnalyst 5.0 (https://www.metaboanalyst.ca/) software for metabolic pathway enrichment analysis. Enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed biosynthesis of unsaturated fatty acids, phenylpropanoid biosynthesis, glycerophospholipid metabolism and phenylalanine, tyrosine and tryptophan biosynthesis as the top predictive metabolic pathways associated with significant phytochemical shifts during germination process. Importantly, our efficacy experimental results dissected that 5 d and 7 d sprouted samples exerted noteworthy inhibitory potentials against acetylcholine esterase (AChE) and monoamine oxidase (MAO-B) enzymes. OPLS-derived coefficients plots portrayed that docosahexaenoic acid, oleic acid, lirioresinol A and tocotrienols dramatically augmented during germination were probably ascribed to promising AChE and MAO-B inhibitory activities. These findings offer a turning point for using pumpkin sprouts with an appreciable biochemical content to pursue the concept of nutritional therapy and accelerate perpetual influx of novel bioproducts to rectify AD.

Ziziphus mauritiana Lam. Bark and Leaves: Extraction, Phytochemical Composition, In Vitro Bioassays and In Silico Studies.

In this work, homogenizer-assisted extraction (HAE) and maceration (MAE) were applied on leaves and bark of Ziziphus mauritiana using water and methanol (MeOH) as solvents. HAE and MAE extracts were compared through liquid chromatography coupled with mass spectrometry (LC-MS) and evaluating the antioxidant activity, and enzyme inhibition against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase. Considering the phytochemical contents and the bioassays results, the HAE extracts resulted favorably with larger content of phenolics and higher antioxidant activity. The MeOH extracts displayed the highest α-amylase inhibitory activity, with HAE MeOH leaf extract leading at 0.78 mmol acarbose equivalent (ACAE)/g. In conclusion, the study highlights that HAE can increase the extraction of phenolic and flavonoid from Z. mauritiana plant materials compared to maceration. Further research could explore the potential therapeutic applications of Z. mauritiana extracts, especially HAE MeOH leaf extracts, for their notable antioxidant and enzyme inhibitory activities, facilitating the way for the development of novel pharmaceutical interventions.

Medicinal perspectives, molecular docking and structure activity relationship of benzothiazole derived thiazole-based bis-benzohydrazide as potential anti-Alzheimer agents

A new series of benzothiazole derived thiazole-based bis-benzohydrazide hybrid (1–20) analogs were synthesized. Initially, the product confirmation was identified by employing TLC and the basic skeleton of the new hybrid synthesized compounds was further confirmed through spectroscopic techniques such as 13CNMR, 1HNMR and HREI-MS. Moreover, the synthesized analogs were tested for their inhibitory activities against acetylcholinesterase and butyrylcholinesterase. In the whole series, compounds 1, 2, 3 and 6 were found with potent activity against acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE). Molecular docking inveatigation of the potent compounds was performed within the active site of acetylcholinesterase and butyrylcholinesterase revealing compounds 1, 2, 3 and 6 showing promising binding orientations against both enzymes as compared to reference drug donepezil with their IC50 values 1(2.20 ± 1.40 and 3.18 ± 0.45 μM), 2 (2.89 ± 1.25 and 2.78 ± 1.49 μM), 3 (2.94 ± 1.10 and 3.07 ± 1.23 μM), 6 (5.83 ± 1.45 and 6.03 ± 3.08 μM), respectively, and reference drug (IC50 = 8.73 ± 2.68 and 9.30 ± 2.60 μM for acetylcholinesterase and butyrylchlinesterase, respectively. In addition, ADME studies were conducted to gain a deeper understanding of the functional mechanisms of a drug on a living organism. It is considered that benzothiazole derived thiazole based bis-benzohydrazide hybrid analogs (1, 2, 3, 6) might be better inhibitors of acetylcholinesterase and butyrylcholinesterase enzymes.

Plant extracts as emerging modulators of neuroinflammation and immune receptors in Alzheimer's pathogenesis

Memory loss is becoming an increasingly significant health problem, largely due to Alzheimer's disease (AD), which disrupts the brain in several ways, including causing inflammation and weakening the body's defenses. This study explores the potential of medicinal plants as a source of novel therapeutic agents for AD.First, we tested various plant extracts against acetylcholinesterase (AChE) in vitro, following molecular docking simulations with key AD-related protein targets such as MAO-B, P-gp, GSK-3β, and CD14. Rosemary extract was found to be the most inhibitory towards AChE. The compounds found in rosemary (oleanolic acid), sage (pinocembrin), and cinnamon (italicene) showed promise in potentially binding to MAO-B. These chemicals may interact with a key protein in the brain and alter the production and removal of amyloid-β. Luteolin (from rosemary), myricetin (from sage), chamigrene, and italicene (from cinnamon) exhibited potential for inhibiting tau aggregation. Additionally, ursolic acid found in rosemary, sage, and chamigrene from cinnamon could modulate CD14 activity.For the first time, our findings shed light on the intricate interplay between neuroinflammation, neuroprotective mechanisms, and the immune system's role in AD. Further research is needed to validate the in vivo efficacy and safety of these plant-derived compounds, as well as their interactions with key protein targets, which could lead to the development of novel AD therapeutics.