Butyrylcholinesterase Research Articles

Chemical profile, antioxidant and anti-Alzheimer activity of leaves and flowers of Markhamia lutea cultivated in Egypt: in vitro and in silico studies

BackgroundNowadays Alzheimer’s disease and its treatment methods are global concerns. Patients with this disease have poor prognosis and need supportive treatment. The antioxidant activity, anti-acetylcholinesterase (anti-AChE), anti-butyryl cholinesterase (anti-BChE) and Aβ-amyloid-42 inhibition activities of the ethanolic extracts of both leaves and flowers (LEE and FEE) of Markhamia lutea were assessed. The antioxidant activity of LEE and FEE was evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate, oxygen radical absorbance capacity and ferrozine iron metal chelation assays. Additionally, their total flavonoids and total phenolics were determined. The phytochemicals of LEE were analysed using LC–MS/Q-TOF in both positive and negative modes. Also, molecular docking was done for phytochemicals identified in LEE.ResultLEE exhibited higher antioxidant and anti-Alzheimer activities in all techniques due to its high flavonoids content. LEE showed better activity than donepezil in case of anti-butyryl cholinesterase than both donepezil and rivastigmine in case of Aβ-amyloid-42 inhibition. A total of 62 compounds were tentatively identified using Ultra-performance Liquid Chromatography-Electrospray Ionization-Quadrupole Time-of-Flight Mass Spectrometry (UHPLC–ESI–TOF–MS), viz. 35 flavonoids, 11 phenolic acids, 2 terpenoids, 2 phenylpropanoids derivatives, 7 polyphenols, 3 coumarins and 2 organic acids. The molecular docking of some constituents showed that isorhamnetin-O-rutinoside, sissotrin, 3,5,7-trihydroxy-4'-methoxyflavone (diosmetin), rosmarinic acid, kaempferol hexoside, kampferol-7-neohesperoside, acacetin, taxifolin and apigenin-O-hexoside exert a promising activity as anti-Alzheimer drugs.ConclusionThe LEE of Markhamia lutea contains secondary metabolites that is promising to act as natural antioxidants, acetylcholinesterase, butyryl cholinesterase and Aβ-amyloid-42 inhibition inhibitors, which can aid in the treatment of Alzheimer’s.Graphical

Inhibitory Effects of Aspirin and Ibuprofen Overdose on Cholinesterase Activity: In Vivo and In Vitro Studies.

In recent years, it has been reported that long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may have protective effects against neurodegenerative diseases by inhibiting the activity of cholinesterase enzymes. The exact biological mechanism of these protective effects is not yet known. This study aims to assess the in vivo and in vitro effects of aspirin and ibuprofen injection on the activity of acetylcholinesterase and butyrylcholinesterase. In this experimental study, 70 adult male mice (20-25 g) were divided randomly into 7 groups (n= 10) including a control group that received normal saline and other groups that received different dosages of aspirin and ibuprofen (100, 200, and 300 mg/kg) in the form of intraperitoneal injection. Mice were anesthetized by ether, and blood samples were taken from the heart. Ellman´s methods were used to measure cholinesterase, erythrocytes, and serum, respectively. The activity of cholinesterase enzymes in serum and erythrocytes decreased significantly (P<0.0001) in treated groups with aspirin and ibuprofen compared to the control samples after 3 and 24 hours. However, these inhibitory effects were variable depending on the dose of the injected drugs, and they were statistically significant at higher injection doses in vitro and in vivo analysis. The result of this study showed that non-steroidal anti-inflammatory drugs can inhibit the activity of the cholinesterase enzymes in both in vivo and in vitro conditions compared to the control group.

Indole alkaloids from Ochreinauclea maingayi (Rubiaceae) as butyrylcholinesterase inhibitors and their paralysis effect in transgenic Caenorhabditis elegans

This study investigated the butyrylcholinesterase (BChE) inhibitory activity of harmane (1), naucledine (2), and dihydrodeglycocadambine (3) isolated from fractions F7 and F9 of Ochreinauclea maingayi. Both fractions demonstrated significant inhibition, exceeding 80%, against BChE at 100 µg/mL. Compound 2, is the most potent inhibitor, exhibiting an IC50 value of 22.08 µM, followed by 1 and 3 (IC50 23.96 and 30.32 µM, respectively). Docking studies revealed that 1 and 2 effectively bind to BChE, with binding energies of −51.24 and −57.17 kcal/mol, respectively. Kinetic analysis of 2 indicated mixed-mode inhibition of BChE, with a Ki of 6.08 μM. In the paralysis assay, 1 showed a weak delay in paralysis and reduced the paralysis ratio from 72.59 ± 4.7% to 60.00 ± 7.0% (12.59% reduction) followed by 2 with 70.00 ± 1.7% (2.59% reduction) compared with negative standard (DMSO 0.1%) on human amyloid β-protein in a transgenic Caenorhabditis elegans (CL4176) model.

Characterization of Phenolic Profile and Biological Properties of Astragalus membranaceus Fisch. ex Bunge Commercial Samples.

Astragalus membranaceus Fisch. ex Bunge (syn. Astragalus mongholicus Bunge) is one of the notable medicinal and food plants. Therefore, the aim of this study was to calculate the phenolic composition and antioxidant, antimicrobial, as well as enzyme inhibitory [acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase (TYR)] activities with chemometric approaches of the hydromethanolic and water extracts of commercial A. membranaceus samples. Ten individual phenolic compounds were determined using high-performance liquid chromatography (HPLC), and only quercetin was found at a level of above 80 µg/g DW in both extracts. Moreover, the highest antioxidant activity in DPPH, FRAP, ABTS, and CUPRAC assays was found in the sample containing the roots in loose form from USA. A. membranaceus extracts displayed the inhibition zone diameters within the range from 10 to 22 mm antimicrobial activity against S. aureus, while there were no inhibition zones in any extracts in case of E. coli. The extracts of A. membranaceous showed an inhibition rate below 40% against TYR, and among tested extracts, only two samples were able to inhibit BChE with IC50 values of above 30 µg/mL. Correlation analysis showed a highly positive relationship between their phenolic composition and antioxidant activity. Concluding, the obtained results confirmed that A. membranaceus commercial samples could be an important dietary source of natural antioxidants.

The enzyme kinetic studies, DNA protection and antioxidant activities of furan/ thiophene-2-carboxamide derivatives

Three furan and/or thiophene-2-carboxamide compounds, namely N-(furan-2-ylmethyl)thiophene-2-carboxamide (1), N-(furan-2-carbonyl)furan-2-carboxamide (2), and N-(Thiophene-2-ylmethyl)furan-2-carboxamide (3) were investigated the enzyme kinetic studies by urease, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The inhibition constant (Ki) of Compound (CPD)3 by AChE was determined as 0.10 mM, and the Ki value by BChE was determined as 0.07 mM. In comparison, the Ki value of CPD1 by urease was determined as 0.10 mM. These CPDs were examined for antioxidant activity by the DPPH˙ scavenging method. CPD3 exhibited 98.93% DPPH scavenging activity compared to ascorbic acid, the positive control group. Furthermore, the DNA-protective activities of the compounds were investigated, and the DNA protection activity of CPD1 was observed to be 78%. The findings suggest that thiophene/furan carboxy amide-containing CPD1 and CPD3 might be exploited as potential structures for evaluating pharmaceuticals with greater potency.

Neuroprotective Effects of Phenolic Constituents from Drynariae Rhizoma.

This study aimed to provide scientific data on the anti-Alzheimer's disease (AD) effects of phenolic compounds from Drynariae Rhizoma (DR) extract using a multi-component approach. Screening of DR extracts, fractions, and the ten phenolic compounds isolated from DR against the key AD-related enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and monoamine oxidase-B (MAO-B) confirmed their significant inhibitory activities. The DR extract was confirmed to have BACE1-inhibitory activity, and the ethyl acetate and butanol fractions were found to inhibit all AD-related enzymes, including BACE1, AChE, BChE, and MAO-B. Among the isolated phenolic compounds, compounds (2) caffeic acid 4-O-β-D-glucopyranoside, (6) kaempferol 3-O-rhamnoside 7-O-glucoside, (7) kaempferol 3-o-b-d-glucopyranoside-7-o-a-L-arabinofuranoside, (8) neoeriocitrin, (9) naringin, and (10) hesperidin significantly suppressed AD-related enzymes. Notably, compounds 2 and 8 reduced soluble Amyloid Precursor Protein β (sAPPβ) and β-secretase expression by over 45% at a concentration of 1.0 μM. In the thioflavin T assay, compounds 6 and 7 decreased Aβ aggregation by approximately 40% and 80%, respectively, and degraded preformed Aβ aggregates. This study provides robust evidence regarding the potential of DR as a natural therapeutic agent for AD, highlighting specific compounds that may contribute to its efficacy.

Fluorescent cyclopropyl ester probes are efficiently cleaved by endogenous carboxylesterase in mouse blood: implications for preclinical fluorescence imaging

ABSTRACT Prior studies have shown that fluorescent molecular probes based on cyclopropyl esters are good substrates for butyrylcholine esterase (BChE), which is a biomarker of several human diseases. We tested two fluorescent cyclopropyl ester derivatives as BChE-activated fluorogenic probes. One was a known fluorescein probe, and the other was a newly designed near-infrared probe based on a heptamethine cyanine dye. As expected, both probes were good substrates for BChE, but they were also good substrates for carboxylesterase (CE). The probes were efficiently cleaved in mouse blood and serum which contains high levels of CE, but they were not cleaved in human serum which contains negligible CE. There are two major implications of these results. One is a cautionary note that esterase levels in different organisms can vary substantially. Researchers developing fluorescent cyclopropyl ester probes for BChE imaging should anticipate high levels of background signal in preclinical mouse models due to ester cleavage by the abundant CE in mouse blood. However, there is very little cleavage of fluorescent cyclopropyl ester probes in human blood, which contains low levels of CE. Therefore, fluorescent cyclopropyl ester probes should be viable in humans as imaging agents that identify disease sites with overexpressed levels of CE or BChE.

A New Class of Benzo[b]thiophene-chalcones as Cholinesterase Inhibitors: Synthesis, Biological Evaluation, Molecular Docking and ADME Studies.

In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a-4i and benzothiophene-chalcone hybrids 5a-5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure-activity relationships. In general, benzothiophene-chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC50 = 62.10 μM) and compound 5h being the best BChE inhibitor (IC50 = 24.35 μM), the last one having an IC50 similar to that of galantamine (IC50 = 28.08 μM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme-inhibitors' interactions.

Essential oils of Plumeria alba L. and Plumeria rubra L. growing in Egypt: GC/MS analysis, molecular dynamics and in-vitro anti-cholinesterase activity

AimEssential oils (EOs) from Plumeria species exhibit noteworthy chemical compositions and diverse biological activities, rendering them valuable constituents for use in medicine, cosmetics, and perfumery. Our aim is to investigate the chemical profiles of P. alba L. and P. rubra L. cultivated in Egypt as biologically active crops. MethodsThe EOs of the flowers of P. alba and P. rubra cultivated in Egypt were prepared by steam distillation and headspace and analyzed by GC/MS. Principal components analysis (PCA) was used to assess the correlation between the chemical composition of the EOs and those reported for EOs of Plumeria species in other countries. ResultsThe score plot revealed a notable difference in the components of EOs prepared by steam distillated and headspace. Geranyl benzoate (27.55 %) was the major compound identified in steam distillated sample of P. alba and linalool (32.52 %) was the major in that prepared by headspace. On the other hand, 1-heptacosanol (23.86 %) was the major compound in the steam distillated sample of P. rubra and 2-methyl-butyl aldoxime (36.38 %) was the major compound in that prepared by headspace. Both EOs demonstrated in-vitro inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Docking study revealed that aromatic compounds have better fitting, while aliphatic compounds have better stability with lower docking interaction energy, and geranyl benzoate showed docking results and binding mode similar to that of the ligands of both enzymes; its stability after docking was confirmed by molecular dynamics. ConclusionEOs from Plumeria species are highly recommended for developing natural and effective aromatherapy products for Alzheimer’s disease.

Butyrylcholinesterase with altered catalytic triad, acting as a promising bioscavenger against organophosphorus agents

Cholinesterases (ChEs) are irreversibly inhibited by organophosphorus compounds (OP) through phosphylation of their active site serine. OPs can be regarded as pseudo-substrates of ChEs in which water-mediated dephosphylation is very slow or impossible. Then, it has been attempted by genetic engineering to convert ChEs into OP hydrolases by speeding up dephosphylation rates. The knowledge of ChEs crystal structure and implementation of potent in silico methods allow rational computer design of new mutants. Such ChE mutants could be used as catalytic bioscavengers in medical counter-measures of OP poisoning. In the present work, using QM/MM MD, we designed a new mutant of human butyrylcholinesterase (BChE). This double mutant, Glu325Gly/Asn322Glu, alters the functioning of the catalytic triad (Ser198.His438.Glu325 in wild-type enzyme), making a new one Ser198.His438.Glu322. Calculations with echothiophate as a model OP showed that the new catalytic triad is stable and capable of hydrolysing the phosphorylated serine. Thus, self-reactivation of the mutated enzyme is possible. Although the calculated dephosphylation rate constant is low, it is expected that the introduction of a third mutation will lead to a much faster turnover.

Design, synthesis, molecular modeling, in vitro evaluation of novel piperidine-containing hydrazone derivatives as cholinesterase inhibitors.

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.

Acetylcholine regulates the melanogenesis of retinal pigment epithelia cells via a cAMP-dependent pathway: A non-neuronal function of cholinergic system in retina

The turnover rate of melanogenesis in retinal pigment epithelium (RPE) and its molecular signaling remain unclear. This study aimed to investigate the role of cholinergic signaling in the process of melanogenesis of cultured RPE cells. Here, a human retinal pigment epithelia cell line, ARPE-19 cell, was used to study the process of melanogenesis. The mRNA and protein expressions of cholinergic molecules, e.g., acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and melanogenic molecules i.e., tyrosinase (TYR), microphthalmia-associated transcription factor (MITF), and melanin pigment were measured during melanogenesis of cultured ARPE-19 cells. Forskolin (a cAMP inducing agent), acetylcholine (ACh) and bethanechol (Bch; a muscarinic AChR agonist) were used to induce melanogenesis in the cultures. Muscarinic acetylcholine receptor (mAChR) antagonists were employed to identify the receptor subtype. During melanogenesis of ARPE-19 cells, the mRNA and protein expressions of cholinergic molecules, e.g., AChE and BChE, were increased along with melanogenic molecules, i.e., TYR, MITF and melanin pigment. Forskolin, ACh, and Bch induced an upregulation of melanogenesis in cultured ARPE-19 cultures: the induction was parallel to an increase of AChE expression. The Bch-induced enzymatic activities and mRNA levels of AChE and TYR were fully blocked by the treatments of gallamine (a M2 specific antagonist), tropicamide (a M4 specific antagonist) and atropine (non-specific antagonist for mAChRs). Cholinergic signaling via M2/M4 mAChRs regulates melanogenesis in cultured ARPE-19 cells through a cAMP-dependent pathway. This study provides insights into the regulation of RPE cell melanogenesis via a non-neuronal function of cholinergic system.

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.

GC-MS-MS analysis and biological properties determination of Mentha piperita L., essential oils

This research explores the therapeutic properties and medicinal potential of Mentha piperita L. (M. piperita) essential oil (EO) (MPEO) harvested in the province of Ouezzane, northwestern Morocco. We conducted a comprehensive chemical composition analysis of MPEO using gas chromatography-mass spectrometry (GC-MS) to identify its major components. The predominant constituents were pulegone (17.56%), mintlactone (10.62%), D-carvone (9.24%), eucalyptol (7.53%), and thymol (6.06%). The antidiabetic effects were assessed by measuring the inhibition of two digestive enzymes (α-glucosidase and α-amylase). The dermatoprotective effect was evaluated based on the inhibition of elastase and tyrosinase, and neuroprotective activity was studied by examining the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Additionally, molecular docking analysis was used to determine the interactions between the main MPEO compounds and the enzymes targeted. Antioxidant activity was estimated using in vitro FRAP, DPPH, and ABTS assays. Furthermore, the antibacterial potential was evaluated against pathogenic strains using the micro-broth dilution method. Our results indicate significant antioxidant and neuroprotective activities of MPEO, along with promising antidiabetic and dermatoprotective potential, surpassing references. Additionally, all bacterial strains tested were susceptible to MPEO, with MIC values lower than those of MBC for all bacteria except L. monocytogenes. These in vitro findings were supported by in silico analysis, showing that menthelactone and pulegone presented strong binding affinities with key enzymes involved in glucose regulation and pigmentation. MPEO, rich in bioactive compounds, has shown promising potential. The main components of this oil offer innovative prospects for the development of drugs and natural therapeutic applications.

Naturally Occurring Cholinesterase Inhibitors from Plants, Fungi, Algae, and Animals: A Review of the Most Effective Inhibitors Reported in 2012-2022.

Since the development of the "cholinergic hypothesis" as an important therapeutic approach in the treatment of Alzheimer's disease (AD), the scientific community has made a remarkable effort to discover new and effective molecules with the ability to inhibit the enzyme acetylcholinesterase (AChE). The natural function of this enzyme is to catalyze the hydrolysis of the neurotransmitter acetylcholine in the brain. Thus, its inhibition increases the levels of this neurochemical and improves the cholinergic functions in patients with AD alleviating the symptoms of this neurological disorder. In recent years, attention has also been focused on the role of another enzyme, butyrylcholinesterase (BChE), mainly in the advanced stages of AD, transforming this enzyme into another target of interest in the search for new anticholinesterase agents. Over the past decades, Nature has proven to be a rich source of bioactive compounds relevant to the discovery of new molecules with potential applications in AD therapy. Bioprospecting of new cholinesterase inhibitors among natural products has led to the discovery of an important number of new AChE and BChE inhibitors that became potential lead compounds for the development of anti-AD drugs. This review summarizes a total of 260 active compounds from 142 studies which correspond to the most relevant (IC50 ≤ 15 μM) research work published during 2012-2022 on plant-derived anticholinesterase compounds, as well as several potent inhibitors obtained from other sources like fungi, algae, and animals.

Effects of Different Physical Training Protocols on Metabolic Syndrome Indicators and the Activity of Butyrylcholinesterase in Adolescents: A Randomized Clinical Trial.

Metabolic syndrome (MS) increases the risk of cardiovascular disease and affects children and adolescents. Butyrylcholinesterase (BChE) is an enzyme associated with obesity. The aim of this study was to investigate the effects of different physical training protocols on MS indicators and their relationship with BChE activity. This randomized clinical trial included 80 adolescents randomly assigned to 4 groups (CG: Control Group; ATG: Aerobic Training Group; STG: Strength Training Group; and CTG: Concurrent Training Group). The EFC, lipid profile, glycemia, waist circumference, and blood pressure were analyzed. With the exception of the CG, all the groups underwent training protocols for 12 consecutive weeks, 4 times a week, as follows: (ATG: 75% of heart rate on an electric treadmill; STG: 85% of 1 maximum repetition; CTG: 20 min of aerobic training at the same intensity as the ATG, and 20 min of resistance training in the same way as the STG). The training reduced MS-related biomarkers, such as the lipid profile, glycemia, waist circumference, and blood pressure. STG reduced BChE activity. The training methods led to improvements in the majority of the MS indicators. In addition, aerobic training significantly reduced BChE activity after a 12-week training protocol. The results suggest that different types of exercise can benefit MS.

Cholinesterase Inhibitory Activity and Molecular Docking Studies of Isocryptolepine-Triazole Adducts.

Due to the rising prevalence of Alzheimer's disease (AD), there is a pressing need for more effective drugs to treat or manage AD's symptoms. Studies have shown that cholinesterase inhibition can improve cognitive and behavioral symptoms associated with AD, by addressing the cholinergic deficit. Based on the recent development of cholinesterase inhibitors with indoloquinoline and triazole moiety, we rationalized that compounds with an isocryptolepine-triazole scaffold may also have the same biological targets. In this study, eighteen previously synthesized isocryptolepine-triazole compounds were assessed for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholine esterase (BChE). The majority of these compounds demonstrated potent selective AChE inhibition. Furthermore, our molecular docking and molecular dynamic simulation studies reveal that the isocryptolepine and triazole moieties are important for the binding of the compounds with the periphery of the AChE's binding pocket. While reductions in molecular weights and lipophilicities may be necessary to improve their pharmacokinetic properties, this work provides valuable insights for designing future AChE inhibitors, based on the novel isocryptolepine-triazole scaffold.

Affinity ultrafiltration based metabolomic profiling directed discovery novel butyrylcholinesterase inhibitors from Uncaria sessilifructus

The butyrylcholinesterase (BChE) is an attractive target for treating Alzheimer's disease. In this study, we report the discovery of five new monoterpene indole alkaloids (MIAs) along with three known analogues from Uncaria sessilifructus Roxb. as BChE inhibitors using affinity ultrafiltration based metabolomic profiling directed isolation strategy. Their structures were well identified through comprehensive spectroscopic and chiroptical analyses. Compounds 1–2 featured unique glycosidic linkages with 1,3-dioxane structure. All the compounds exhibited BChE inhibitory bioactivity without any cytotoxic effects. Enzymatic kinetic and molecular docking analyses of compounds 1 and 6 demonstrated their inhibiting mechanisms and binding patterns to BChE. These findings provide a valuable workflow for efficiently screening ligands that bind to proteins, and scientific recognition in the discovery of BChE inhibitors for treating neurodegenerative disorders.

Design of New Aromatic Tertiary Amine-based as Butyrylcholinesterase Inhibitors Relying on Molecular Docking, ADME-Tox and Molecular Dynamics.

Butyrylcholinesterase (BChE) plays a pivotal role in the progression of Alzheimer's disease. Empirical research demonstrated a fundamental alteration in the role of BChE concerning the reduction of cholinergic neurotransmission within the brains of individuals at advanced stages of Alzheimer's. This study focuses on developing potent inhibitors for Butyrylcholinesterase (BChE) in the context of Alzheimer's disease (AD) treatment. Building upon previous research, a series of 44 aromatic tertiary amine-based compounds was investigated. Starting with ADME-Tox studies, the pharmacokinetic and pharmacodynamic properties of the compounds were analyzed to select promising candidates for BChE inhibition, which is a crucial factor in AD pathology. Molecular docking analyses identified compound M18 as the most promising candidate, and further compounds (X9 and X10) were proposed based on M18's chemical structure. These compounds displayed superior properties in terms of binding energies and hydrogen bonds in comparison to M18. The Molecular Dynamics (MD) simulations, which are over a 500 ns timeframe, confirmed the conformational stability of compounds X9 and X10, compared to M18. Overall, the stated results suggest that the proposed compounds, including X9 and X10 specifically, have a significant potential as candidates for BChE inhibition. This presents a promising avenue for therapeutic intervention in Alzheimer's disease.

Development of Delivery Systems with Prebiotic and Neuroprotective Potential of Industrial-Grade Cannabis sativa L.

This study delves into the transformative effects of supercritical carbon dioxide (scCO2) cannabis extracts and prebiotic substances (dextran, inulin, trehalose) on gut bacteria, coupled with a focus on neuroprotection. Extracts derived from the Białobrzeska variety of Cannabis sativa, utilising supercritical fluid extraction (SFE), resulted in notable cannabinoid concentrations (cannabidiol (CBD): 6.675 ± 0.166; tetrahydrocannabinol (THC): 0.180 ± 0.006; cannabigerol (CBG): 0.434 ± 0.014; cannabichromene (CBC): 0.490 ± 0.017; cannabinol (CBN): 1.696 ± 0.047 mg/gD). The assessment encompassed antioxidant activity via four in vitro assays and neuroprotective effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract boasting the highest cannabinoid content exhibited remarkable antioxidant potential and significant inhibitory activity against both enzymes. Further investigation into prebiotic deliveries revealed their proficiency in fostering the growth of beneficial gut bacteria while maintaining antioxidant and neuroprotective functionalities. This study sheds light on the active compounds present in the Białobrzeska variety, showcasing their therapeutic potential within prebiotic systems. Notably, the antioxidant, neuroprotective, and prebiotic properties observed underscore the promising therapeutic applications of these extracts. The results offer valuable insights for potential interventions in antioxidant, neuroprotective, and prebiotic domains. In addition, subsequent analyses of cannabinoid concentrations post-cultivation revealed nuanced changes, emphasising the need for further exploration into the dynamic interactions between cannabinoids and the gut microbiota.