Butyrylcholinesterase Research Articles

2-amino-6-ethoxy-4-arylpyridine-3,5-dicarbonitrile Scaffolds as potential acetylcholinesterase and butyrylcholinesterase inhibitors

Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are of prime importance for treating Alzheimerʼs disease (AD). Apart from many organic scaffolds, pyridine-based compounds have previously been reported as potential α-glucosidase inhibitors. The current study reports a series of pyridine-based synthetic molecules for their acetylcholinesterase AChE and butyrylcholinesterase BChE inhibitory potential assessed via in vitro, kinetics, and in silico studies. For this purpose, 2-amino-6-ethoxy-4-arylpyridine-3,5-dicarbonitrile analogs 1–23 were synthesized by using a two-step reaction scheme. In the first step, different aryl aldehydes were treated with malononitrile to afford the 2-benzylidenemalononitrile in the presence of catalyst ammonium acetate. In the next step, 2-benzylidenemalononitrile intermediates were reacted again with malononitrile, catalyzed by potassium hydroxide, to synthesize a range of functionalized pyridine scaffolds in good yields. Compounds were subjected to in vitro screening against AChE and BChE enzymes. Several derivatives, including 2, 3, 11, 14–16, 19, 20, and 22, showed many folds of increased inhibitory potential and binding affinity in the ranges of Ki = 1.62 ± 0.13 nM to 15.84 ± 0.10 nM for AChE and Ki = 1.35 ± 0.31 nM to 13.52 ± 0.61 nM for BChE, as compared to the standard tacrine Ki = 53.31 ± 11.32 nM for AChE, and Ki = 58.16 ± 7.24 nM for BChE. Further, molecular docking studies deduced key interactions between the ligands (compounds) and the active pocket of enzymes. The current research study has identified several potential AChE and BChE inhibitors that may serve as lead candidates after targeted advanced research for exploring anti-Alzheimer agents.

Supercritical carbon dioxide extracts of Schinus terebinthifolia fruits and their utilization against microbial illness, lipase, and butyrylcholinesterase activities in vitro

Supercritical carbon dioxide extracts of Schinus terebinthifolia fruits and their utilization against microbial illness, lipase, and butyrylcholinesterase activities in vitro

Bis-chalcones obtained via one-pot synthesis as the anti-neurodegenerative agents and their effect on the HT-22 cell line

In the area of research on neurodegenerative diseases, the current challenge is to search for appropriate research methods that would detect these diseases at the earliest possible stage, but also new active structures that would reduce the rate of the disease progression and minimize the intensity of their symptoms experienced by the patient. The chalcones are considered in the context of candidates for new drugs dedicated to the fight against neurodegenerative diseases. The synthesis of bis-chalcone derivatives (3a-3d), as aim molecules was performed. Their structures were established by applying 1H NMR, 13C NMR, MS, FT-IR and UV–Vis spectra. All bis-chalcones were synthesized from terephthalaldehyde and appropriate aromatic ketone as substrates in the Claisen-Schmidt condensation method and evaluated in the biological tests and in silico analysis. Compounds exerted antioxidant activity using the HORAC method (3a-3d) and decreased the activities of GPx, COX-2 (3b-3d), GR (3a-3c) and CAT (3a,3b). The high anti-neurodegenerative potential of all four bis-chalcones was observed by inhibition of acetyl- (AChE) and butyrylcholinesterase (BChE) and a positive effect on the mouse hippocampal neuronal HT-22 cell line (LDH release and PGC-1α, PPARγ and GAPDH protein expression). TD-DFT method (computing a number of descriptors associated with HOMO–LUMO electron transition: electronegativity, chemical hardness and potential, first ionization potential, electron affinity) was employed to study the spectroscopic properties. This method showed that the first excited state of compounds was consistent with their maximum absorption in the computed UV–Vis spectra, which showed good agreement with the experimental spectrum using PBE1PBE functional. Using in silico approach, interactions of bis-chalcones with selected targets (aryl hydrocarbon receptor (AhR) PAS-A Domain, ligand binding domain of human PPAR-γ, soman-aged human BChE-butyrylthiocholine complex, Torpedo californica AChE:N-piperidinopropyl-galanthamine complex and the COX-2-celecoxib complex) were characterized. Results obtained in in silico models were consistent with in vitro experiments.

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.

Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer's Disease: Their Design, Synthesis, and In-Vitro and In-Silico Investigations.

Alzheimer's Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes. The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman's spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted. Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 μM, 0.096 μM, and 0.177 μM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied. Overall, this research contributes to the development of 1,3,4-oxadiazole- quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer's disease.

Chemical Composition, Cholinesterase Inhibitory Effect and Cytotoxic Activity Study of Essential Oils Extracted from Different Parts of Satureja isophylla Rech.f

Background: Based on available literature, no study has yet considered the phytochemical profile and pharmacological activities of essential oils extracted from different parts of Satureja isophylla. Objectives: This study aimed to investigate the chemical composition, cholinesterase (ChE) inhibitory effects, and cytotoxic activities of essential oils extracted from different parts of Satureja isophylla. Methods: Essential oils extracted from the flowers, leaves, stems, and roots of Satureja isophylla, which is endemic to Iran, were separately analyzed using GC-MS. The ChE inhibitory activities of these extracts were tested on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The growth-inhibitory effects of the extracts were assessed against four cancer cell lines: MCF-7, ACHN, AsPC-1, and PC-12. Results: GC-MS analysis identified a total of 51 compounds from different parts of the plant, with α-eudesmol, camphor, elemol, and γ-eudesmol being the main components. The ChE inhibitory activity results indicated significant inhibition of BChE compared to AChE. The essential oils exhibited greater toxicity against AsPC-1 cells compared to other cancer cell lines in the MTT assay. Conclusions: This study is the first to examine the chemical composition and therapeutic effects of essential oils extracted from various parts of Satureja isophylla. Further research is needed to explore additional pharmacological activities and to provide a more comprehensive phytochemical profile of this plant.

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.

Repurposing Duloxetine as a Potent Butyrylcholinesterase Inhibitor: Potential Cholinergic Enhancing Benefits for Elderly Individuals with Depression and Cognitive Impairment.

Despite the advent of new treatment strategies, cholinesterase inhibitors (ChEIs) are still the go-to treatment for dementia disorders. ChEIs act by inhibiting the main acetylcholine-degrading enzyme, acetylcholinesterase (AChE). Nonetheless, accumulating evidence indicates that the impact of inhibition of the sister enzyme, butyrylcholinesterase (BChE), could be even broader in older adults due to the multifaceted role of BChE in several biological functional pathways. Therefore, we employed an in silico modeling-based drug repurposing strategy to identify novel potent BChE inhibitors from the FDA drug database. This was followed by in vitro screening and ex vivo enzyme kinetic validation using human plasma samples as the source of BChE. The analysis revealed that the antidepressant drug, duloxetine, inhibited BChE with high selectivity in comparison to AChE. In contrast, two other antidepressants, namely, citalopram and escitalopram exhibited a weak to moderate activity. Ex vivo enzyme inhibition kinetic analyses indicated that duloxetine acted as a competitive inhibitor of BChE with an inhibition constant (K i) of 210 nM. This K i value is comparable with 100-400 nM concentration of duloxetine following normal dosages in humans, thereby indicating that duloxetine should be able to induce a pharmacologically and biologically relevant in vivo inhibition of BChE. Additionally, we performed the enzyme inhibition kinetic assessment in parallel for ethopropazine, a known potent selective BChE inhibitor, and physostigmine, a dual inhibitor of AChE and BChE. These analyses indicated that duloxetine should be considered a potent BChE inhibitor since its K i was comparable with ethopropazine (K i = 150 nM) but was 4 times smaller than that of physostigmine (K i = 840 nM). In conclusion, this study reports the discovery of duloxetine being a highly potent selective competitive BChE inhibitor. This, in turn, indicates that duloxetine could be the choice of antidepressive treatment in older adults with both depressive and dementia symptoms since it may offer additional clinically beneficial effects via this secondary mode of cholinergic enhancing action.

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.

Butyrylcholinesterase levels correlate with surgical site infection risk and severity after colorectal surgery: a prospective single-center study.

Surgical site infections (SSIs) after colorectal surgery remain a significant concern, which warrants effective predictive markers for prompt diagnosis and treatment. Butyrylcholinesterase (BChE), a non-specific cholinesterase enzyme, has been correlated with the risk of hepatic dysfunction progression and, more recently, infectious diseases and septic shock with ongoing research into the utility of BChE in multiple systemic inflammatory conditions. Whether these preliminary results can be translated into predicting infection after colorectal surgery remains in remains in question. This prospective study aimed to assess BChE's potential as a predictive marker for surgical site infections and anastomotic leaks after colorectal surgery. This single-center prospective study (11/2019-05/2023) enrolled 402 patients who underwent colorectal surgery. BChE levels were measured at four postoperative time points. The primary endpoints focused on BChE's association with complications, particularly surgical site infections (SSIs). Further known predictors of SSI were utilized to construct multivariable models to assess for independent association with SSI development. During the third and fifth day postsurgery, SSI patients had significantly lower mean BChE levels (3.90 KU/L vs. 4.54 KU/L p-value < 0.05, and 4.14 KU/L vs. 4.73 KU/L, p-value < 0.05; t-test, respectively). However, multivariate analysis revealed that when adjusted for other factors, low BChE levels on the first postoperative day were associated with 2.6 times higher odds of developing SSI (OR: 2.6, 95%CI: 1.3-3.9, p-value < 0.05). Similar results were found for low BChE levels on the third postoperative day as they were associated with a. 2.53 times higher odds for developing SSI (OR: 2.5, 95%CI: 1.27-3.87, p-value < 0.05) when adjusted for other factors. In conclusion, in this prospective observational study, low levels in the first and third postsurgery were associated with an increased risk for the development of SSIs but not sepsis.

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.