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13C NMR-based dereplication using MixONat software to decipher potent anti-cholinesterase compounds in Mesua lepidota bark

Leong ST, Liew SY, Khaw KY, Ahmad Hassali H, Richomme P, Derbré S, et al.

Bioorg Chem, 2023 Dec;141:106859.
PMID: 37742494 DOI: 10.1016/j.bioorg.2023.106859

A bio-assay guided fractionation strategy based on cholinesterase assay combined with 13C NMR-based dereplication was used to identify active metabolites from the bark of Mesua lepidota. Eight compounds were identified with the aid of the 13C NMR-based dereplication software, MixONat, i.e., sitosterol (1), stigmasterol (2), α-amyrin (3), friedelin (6), 3β-friedelinol (7), betulinic acid (9), lepidotol A (10) and lepidotol B (11). Further bio-assay guided isolation of active compounds afforded one xanthone, pyranojacareubin (12) and six coumarins; lepidotol A (10), lepidotol B (11), lepidotol E (13), lepidotin A (14), and lepidotin B (15), including a new Mammea coumarin, lepidotin C (16). All the metabolites showed strong to moderate butyrylcholinesterase (BChE) inhibition. Lepidotin B (15) exhibited the most potent inhibition towards BChE with a mix-mode inhibition profile and a Ki value of 1.03 µM. Molecular docking and molecular dynamics simulations have revealed that lepidotin B (15) forms stable interactions with key residues within five critical regions of BChE. These regions encompass residues Asp70 and Tyr332, the acyl hydrophobic pocket marked by Leu286, the catalytic triad represented by Ser198 and His438, the oxyanion hole (OH) constituted by Gly116 and Gly117, and the choline binding site featuring Trp82. To gauge the binding strength of lepidotin B (15) and to pinpoint pivotal residues at the binding interface, free energy calculations were conducted using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) approach. This analysis not only predicted a favourable binding affinity for lepidotin B (15) but also facilitated the identification of significant residues crucial for the binding interaction.

Matched MeSH terms: Acetylcholinesterase/metabolism
Fulltext Phytochemical Compounds and Nanoparticles as Phytochemical Delivery Systems for Alzheimer's Disease Management

Bakrim S, Aboulaghras S, El Menyiy N, El Omari N, Assaggaf H, Lee LH, et al.

Molecules, 2022 Dec 19;27(24).
PMID: 36558176 DOI: 10.3390/molecules27249043

Alzheimer's disease remains one of the most widespread neurodegenerative reasons for dementia worldwide and is associated with considerable mortality and morbidity. Therefore, it has been considered a priority for research. Indeed, several risk factors are involved in the complexity of the therapeutic ways of this pathology, including age, traumatic brain injury, genetics, exposure to aluminum, infections, diabetes, vascular diseases, hypertension, dyslipidemia, and obesity. The pathophysiology of Alzheimer's disease is mostly associated with hyperphosphorylated protein in the neuronal cytoplasm and extracellular plaques of the insoluble β-amyloid peptide. Therefore, the management of this pathology needs the screening of drugs targeting different pathological levels, such as acetylcholinesterase (AchE), amyloid β formation, and lipoxygenase inhibitors. Among the pharmacological strategies used for the management of Alzheimer's disease, natural drugs are considered a promising therapeutic strategy. Indeed, bioactive compounds isolated from different natural sources exhibit important anti-Alzheimer effects by their effectiveness in promoting neuroplasticity and protecting against neurodegeneration as well as neuroinflammation and oxidative stress in the brain. These effects involve different sub-cellular, cellular, and/or molecular mechanisms, such as the inhibition of acetylcholinesterase (AchE), the modulation of signaling pathways, and the inhibition of oxidative stress. Moreover, some nanoparticles were recently used as phytochemical delivery systems to improve the effects of phytochemical compounds against Alzheimer's disease. Therefore, the present work aims to provide a comprehensive overview of the key advances concerning nano-drug delivery applications of phytochemicals for Alzheimer's disease management.

Matched MeSH terms: Acetylcholinesterase/metabolism
Fulltext In Silico and In Vitro Methods in the Characterization of Beta-Carotene as Pharmaceutical Material via Acetylcholine Esterase Inhibitory Actions

Muthuraman A, Ramesh M, Mustaffa F, Nadeem A, Nishat S, Paramakrishnan N, et al.

Molecules, 2023 May 26;28(11).
PMID: 37298835 DOI: 10.3390/molecules28114358

Molecular docking is widely used in the assessment of the therapeutic potential of pharmaceutical agents. The binding properties of beta-carotene (BC) to acetylcholine esterase (AChE) proteins were characterized using the molecular docking method. The mechanism of AChE inhibition was assessed by an experimental in vitro kinetic study. In addition, the role of BC action was tested by the zebrafish embryo toxicity test (ZFET). The results of the docking ability of BC to AChE showed significant ligand binding mode. The kinetic parameter, i.e., the low AICc value shown as the compound was the competitive type of inhibition of AChE. Further, BC also showed mild toxicity at a higher dose (2200 mg/L) in ZFET assessment with changes in biomarkers. The LC50 value of BC is 1811.94 mg/L. Acetylcholine esterase (AChE) plays a pivotal role in the hydrolysis of acetylcholine, which leads to the development of cognitive dysfunction. BC possesses the regulation of acetylcholine esterase (AChE) and acid phosphatase (AP) activity to prevent neurovascular dysfunction. Therefore, the characterization of BC could be used as a pharmaceutical agent for the treatment of cholinergic neurotoxicity-associated neurovascular disorders such as developmental toxicity, vascular dementia, and Alzheimer's disease due to its AChE and AP inhibitory actions.

Matched MeSH terms: Acetylcholinesterase/metabolism
Study on the neurotoxicity of the temephos impregnated kenaf cellulose nanofiber (KCNF+T) aerosols against the female Aedes aegypti mosquitoes

Sabri N, Kamaldin J, Sivanathan M, Rasli R

Trop Biomed, 2024 Sep 01;41(3):283-289.
PMID: 39548782 DOI: 10.47665/tb.41.3.008

The study has generated visible aerosols with the diameter of 11 to 35 µm from the kenaf cellulose nanofiber (KCNF) impregnated with the temephos (KCNF+T) in water suspension. The study aimed to determine whether the KCNF+T aerosols are capable to elicit neurotoxicity in the adult mosquitoes via the respiratory exposure route by observing their behavioural response and measuring its body acetylcholine esterase (AChE) activity. Adult Aedes aegypti mosquitoes were assigned to one negative control group and three treatment groups namely, distilled water (vehicle control), KCNF and KCNF+T. The study adopted the MS1911 whereby the aerosols generated are released into the insecticide bioassay glass chamber (IBGC) separately to achieve four different aerosols concentrations of 6.4 ml/m3, 12.8 ml/m3, 19.2 ml/m3, and 25.6 ml/m3. Then the 20 sugar-fed mosquitoes were released free-flying into each IBGC to observe its behavioural response (knockdown) at 30, 60, 120, 180, 240, 300 minutes intervals and 24th hour mortality. Results showed that only mosquitoes exposed to KCNF+T aerosols exhibited persistent knockdown. There was significant difference (p< 0.05) between observation intervals with the cumulative knockdown of 84.8%, 92.8%, 99.0%, 100.0%, 100.0%, 100.0% compared with the KCNF aerosols. Further, it was distinctive that only KCNF+T is capable to cause the female mosquitoes moribund/mortality at the 24th hour with 90% at the lowest aerosol concentration of 6.4 ml/m3. The neuroenzyme assay on the mosquito that died from the KCNF+T exposure verified to have reduced AChE enzyme activity. The behavioural response and reduction of the AChE activity strongly suggests the temephos from the KCNF+T aerosols has been released into the mosquito body causing the neurotoxicity but KCNF alone is not neurotoxic.

Matched MeSH terms: Acetylcholinesterase/metabolism
Fulltext Enzymatic characterization of insecticide resistance mechanisms in field populations of Malaysian Culex quinquefasciatus say (Diptera: Culicidae)

Low VL, Chen CD, Lee HL, Tan TK, Chen CF, Leong CS, et al.

PLoS One, 2013;8(11):e79928.
PMID: 24278220 DOI: 10.1371/journal.pone.0079928

There has been no comprehensive study on biochemical characterization of insecticide resistance mechanisms in field populations of Malaysian Culex quinquefasciatus. To fill this void in the literature, a nationwide investigation was performed to quantify the enzyme activities, thereby attempting to characterize the potential resistance mechanisms in Cx. quinquefasciatus in residential areas in Malaysia.

Matched MeSH terms: Acetylcholinesterase/metabolism*
Fulltext Synthesis, characterization, acetylcholinesterase inhibition, molecular modeling and antioxidant activities of some novel Schiff bases derived from 1-(2-ketoiminoethyl)piperazines

Salga SM, Ali HM, Abdullah MA, Abdelwahab SI, Wai LK, Buckle MJ, et al.

Molecules, 2011 Nov 07;16(11):9316-30.
PMID: 22064271 DOI: 10.3390/molecules16119316

Some novel Schiff bases derived from 1-(2-ketoiminoethyl)piperazines were synthesized and characterized by mass spectroscopy, FTIR, UV-Visible, 1H and 13C-NMR. The compounds were tested for inhibitory activities on human acetylcholinesterase (hAChE), antioxidant activities, acute oral toxicity and further studied by molecular modeling techniques. The study identified the compound (DHP) to have the highest activity among the series in hAChE inhibition and DPPH assay while the compound LP revealed the highest activity in the FRAP assay. The hAChE inhibitory activity of DHP is comparable with that of propidium, a known AChE inhibitor. This high activity of DHP was checked by molecular modeling which showed that DHP could not be considered as a bivalent ligand due to its incapability to occupy the esteratic site (ES) region of the 3D crystal structure of hAChE. The antioxidant study unveiled varying results in 1,1-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. This indicates mechanistic variations of the compounds in the two assays. The potential therapeutic applications and safety of these compounds were suggested for use as human acetylcholinesterase inhibitors and antioxidants.

Matched MeSH terms: Acetylcholinesterase/metabolism
Effect of acute noise stress on acetylcholinesterase activity in discrete areas of rat brain

Sembulingam K, Sembulingam P, Namasivayam A

Indian J Med Sci, 2003 Nov;57(11):487-92.
PMID: 14646156

Effect of various stressor agents on the adrenergic system in brain had been studied extensively. However, reports on the effect of stress on various parameters of central cholinergic system are scanty. And very little is known about the effect of noise stress on the cholinergic system in brain. Hence, it was decided to elucidate the effect of acute noise stress on the activity of the enzyme acetylcholinesterase in discrete areas of brain in albino rats. Male albino rats of Wistar strain were subjected to acute noise stress for 30 minutes. The noise of pure sine wave tone was produced by using a function generator and was amplified. The frequency of noise generated was 1 kHz and the intensity was set at 100 dB. The total acetylcholinesterase activity was determined in the tissues of cerebral cortex, corpus striatum, hypothalamus and hippocampus of brain in these rats. The enzyme activity was estimated by colorimetric method using acetylthiocholine iodide as the substrate. The values were compared with the enzyme activity in the control rats. The activity of the enzyme increased significantly in all the four regions of the brain in rats after exposure to noise stress for 30 minutes. The results of the study indicate that the exposure to acute noise stress could modulate the cholinergic system in these areas of brain in rat.

Matched MeSH terms: Acetylcholinesterase/metabolism*
Fulltext Palm Oil Derived Tocotrienol-Rich Fraction Attenuates Vascular Dementia in Type 2 Diabetic Rats

Shaikh SA, Varatharajan R, Muthuraman A

Int J Mol Sci, 2022 Nov 04;23(21).
PMID: 36362316 DOI: 10.3390/ijms232113531

Vascular dementia (VaD) is a serious global health issue and type 2 diabetes mellitus (T2DM) patients are at higher risk. Palm oil tocotrienol-rich fraction (TRF) exhibits neuroprotective properties; however, its effect on VaD is not reported. Hence, we evaluated TRF effectiveness in T2DM-induced VaD rats. Rats were given a single dose of streptozotocin (STZ) and nicotinamide (NA) to develop T2DM. Seven days later, diabetic rats were given TRF doses of 30, 60, and 120 mg/kg orally for 21 days. The Morris water maze (MWM) test was performed for memory assessment. Biochemical parameters such as blood glucose, plasma homocysteine (HCY) level, acetylcholinesterase (AChE) activity, reduced glutathione (GSH), superoxide dismutase (SOD) level, and histopathological changes in brain hippocampus and immunohistochemistry for platelet-derived growth factor-C (PDGF-C) expression were evaluated. VaD rats had significantly reduced memory, higher plasma HCY, increased AChE activity, and decreased GSH and SOD levels. However, treatment with TRF significantly attenuated the biochemical parameters and prevented memory loss. Moreover, histopathological changes were attenuated and there was increased PDGF-C expression in the hippocampus of VaD rats treated with TRF, indicating neuroprotective action. In conclusion, this research paves the way for future studies and benefits in understanding the potential effects of TRF in VaD rats.

Matched MeSH terms: Acetylcholinesterase/metabolism
Fulltext Multipotent Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease: Synthesis, Biological Analysis and Molecular Docking Study of Benzimidazole-Based Thiazole Derivatives

Hussain R, Ullah H, Rahim F, Sarfraz M, Taha M, Iqbal R, et al.

Molecules, 2022 Sep 18;27(18).
PMID: 36144820 DOI: 10.3390/molecules27186087

Twenty-four analogues of benzimidazole-based thiazoles (1-24) were synthesized and assessed for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potential. All analogues were found to exhibit good inhibitory potential against cholinesterase enzymes, having IC50 values in the ranges of 0.10 ± 0.05 to 11.10 ± 0.30 µM (for AChE) and 0.20 ± 0.050 µM to 14.20 ± 0.10 µM (for BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 and 4.5 ± 0.11 µM, respectively). Among the series, analogues 16 and 21 were found to be the most potent inhibitors of AChE and BuChE enzymes. The number (s), types, electron-donating or -withdrawing effects and position of the substituent(s) on the both phenyl rings B & C were the primary determinants of the structure-activity relationship (SAR). In order to understand how the most active derivatives interact with the amino acids in the active site of the enzyme, molecular docking studies were conducted. The results obtained supported the experimental data. Additionally, the structures of all newly synthesized compounds were elucidated by using several spectroscopic methods like 13C-NMR, 1H-NMR and HR EIMS.

Matched MeSH terms: Acetylcholinesterase/metabolism
Development of an inhibitive assay using commercial Electrophorus electricus acetylcholinesterase for heavy metal detection

Shukor MY, Tham LG, Halmi MI, Khalid I, Begum G, Syed MA

J Environ Biol, 2013 Sep;34(5):967-70.
PMID: 24558814

Near-real-ime assay is anassay method that the whole process from sampling until results could be obtained in approximately Iess than one hour. The ElIman assay for acetyl cholinesterase (AChE) has near real-time potential due to its simplicity and fast assay time. The commercial acetylcholinesterase from Electrophorus electricus is well known for its uses in insecticides detection. A lesser known fact is AChE is also sensitive to heavy metals. A near real-time inhibitive assay for heavy metals using AChE from this source showed promising results. Several heavy metals such as copper, silver and mercury could be etected with IC50 values of1.212, 0.1185 and 0.097 mg I-1, respectively. The Limits of Detection (LOD) for copper, silver and mercury were 0.01, 0.015 and 0.01 mg I-1, respectively. TheLimits of quantitation (LOQ) or copper, silver and mercury were 0.196, 0.112 and 0.025 mg I-1, respectively. The LOQvalues for copper, silver and mercury were well below the maximum permissible limit for these metal ions as outlined by Malaysian Department of Environment. A polluted location demonstrated near real-time applicability of the assay with variation oftemporal levels of heavy metals detected. The results show that AChE from Electrophorus electricus has the potential to be used as a near real-time biomonitoring tool for heavy

Matched MeSH terms: Acetylcholinesterase/metabolism*
4-Phenylcoumarins from Mesua elegans with acetylcholinesterase inhibitory activity

Awang K, Chan G, Litaudon M, Ismail NH, Martin MT, Gueritte F

Bioorg Med Chem, 2010 Nov 15;18(22):7873-7.
PMID: 20943395 DOI: 10.1016/j.bmc.2010.09.044

A significant acetylcholinesterase (AChE) inhibitory activity was observed for the hexane extract from the bark of Mesua elegans (Clusiaceae). Thus, the hexane extract was subjected to chemical investigation, which led to the isolation of nine 4-phenylcoumarins, in which three are new; mesuagenin A (1), mesuagenin C (3), mesuagenin D (4) and one new natural product; mesuagenin B (2). The structures of the isolated compounds were characterized by spectroscopic data interpretation, especially 1D and 2D NMR. Four compounds showed significant AChE inhibitory activity, with mesuagenin B (2) being the most potent (IC(50)=0.7μM).

Matched MeSH terms: Acetylcholinesterase/metabolism
A bioactive cycloartane triterpene from Garcinia hombroniana

Jamila N, Khan N, Khan I, Khan AA, Khan SN

Nat Prod Res, 2016 Jun;30(12):1388-97.
PMID: 26158779 DOI: 10.1080/14786419.2015.1060594

The dichloromethane bark extract of Garcinia hombroniana yielded one new cycloartane triterpene; (22Z,24E)-3β-hydroxycycloart-14,22,24-trien-26-oic acid (1) together with five known compounds: garcihombronane G (2), garcihombronane J (3), 3β acetoxy-9α-hydroxy-17,14-friedolanostan-14,24-dien-26-oic acid (4), (22Z, 24E)-3β, 9α-dihydroxy-17,14-friedolanostan-14,22,24-trien-26-oic acid (5) and 3β, 23α-dihydroxy-17,14-friedolanostan-8,14,24-trien-26-oic acid (6). Their structures were established by the spectral techniques of NMR and ESI-MS. These compounds together with some previously isolated compounds; garcihombronane B (7), garcihombronane D (8) 2,3',4,5'-tetrahydroxy-6-methoxybenzophenone (9), volkensiflavone (10), 4''-O-methyll-volkensiflavone (11), volkensiflavone-7-O-glucopyranoside (12), volkensiflavone-7-O-rhamnopyranoside (13), Morelloflavone (14), 3''-O-methyl-morelloflavone (15) and morelloflavone-7-O-glucopyranoside (16) were evaluated for cholinesterase enzymes inhibitory activities using acetylcholinesterase and butyrylcholinesterase. In these activities, compounds 1-9 showed good dual inhibition on both the enzymes while compounds 10-16 did not reasonably contribute to both the cholinesterases inhibitory effects.

Matched MeSH terms: Acetylcholinesterase/metabolism
Design, synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase

Wu J, Pistolozzi M, Liu S, Tan W

Bioorg Med Chem, 2020 03 01;28(5):115324.
PMID: 32008882 DOI: 10.1016/j.bmc.2020.115324

Rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), has been approved by U.S. Food and Drug Administration to treat Alzheimer's disease (AD) and Parkinson's disease (PD) dementia. In the current work, a bambuterol derivative lacking one of the carbamoyloxy groups on the benzene ring (BMC-1) and its analogues were synthesized using 1-(3-hydroxyphenyl) ethan-1-one and 1-(4-hydroxyphenyl) ethan-1-one as starting materials. In-vitro cholinesterase assay established that nine compounds were more potent to inhibit both electric eel AChE and equine serum BChE than rivastigmine under the same experimental conditions. Further study confirmed that among the nine carbamates, BMC-3 (IC50(AChE) = 792 nM, IC50(BChE) = 2.2 nM) and BMC-16 (IC50(AChE) = 266 nM, IC50(BChE) = 10.6 nM) were excellent cholinesterase inhibitors with potential of permeating through the blood-brain barrier. These carbamates could be used as potential dual inhibitors of AChE and BChE and to discover novel drugs for the treatment of AD and PD dementia.

Matched MeSH terms: Acetylcholinesterase/metabolism*
Interspecific and intraspecific venom enzymatic variation among cobras (Naja sp. and Ophiophagus hannah)

Modahl CM, Roointan A, Rogers J, Currier K, Mackessy SP

Comp Biochem Physiol C Toxicol Pharmacol, 2020 Jun;232:108743.
PMID: 32194156 DOI: 10.1016/j.cbpc.2020.108743

The genera Ophiophagus and Naja comprise part of a clade of snakes referred to as cobras, dangerously venomous front-fanged snakes in the family Elapidae responsible for significant human mortality and morbidity throughout Asia and Africa. We evaluated venom enzyme variation for eleven cobra species and three N. kaouthia populations using SDS-PAGE venom fingerprinting and numerous enzyme assays. Acetylcholinesterase and PLA2 activities were the most variable between species, and PLA2 activity was significantly different between Malaysian and Thailand N. kaouthia populations. Venom metalloproteinase activity was low and significantly different among most species, but levels were identical for N. kaouthia populations; minor variation in venom L-amino acid oxidase and phosphodiesterase activities were seen between cobra species. Naja siamensis venom lacked the α-fibrinogenolytic activity common to other cobra venoms. In addition, venom from N. siamensis had no detectable metalloproteinase activity and exhibited an SDS-PAGE profile with reduced abundance of higher mass proteins. Venom profiles from spitting cobras (N. siamensis, N. pallida, and N. mossambica) exhibited similar reductions in higher mass proteins, suggesting the evolution of venoms of reduced complexity and decreased enzymatic activity among spitting cobras. Generally, the venom proteomes of cobras show highly abundant three-finger toxin diversity, followed by large quantities of PLA2s. However, PLA2 bands and activity were very reduced for N. haje, N. annulifera and N. nivea. Venom compositionalenzy analysis provides insight into the evolution, diversification and distribution of different venom phenotypes that complements venomic data, and this information is critical for the development of effective antivenoms and snakebite treatment.

Matched MeSH terms: Acetylcholinesterase/metabolism*
Anti-Cholinesterase Activity of Chalcone Derivatives: Synthesis, In Vitro Assay and Molecular Docking Study

Riswanto FDO, Rawa MSA, Murugaiyah V, Salin NH, Istyastono EP, Hariono M, et al.

Med Chem, 2021;17(5):442-452.
PMID: 31808389 DOI: 10.2174/1573406415666191206095032

BACKGROUND: Chalcones, originated from natural product, have been broadly studied their biological activity against various proteins which at the molecular level, are responsible for the progress of the diseases in cancer (e.g. kinases), inflammation (oxidoreductases), atherosclerosis (cathepsins receptor), and diabetes (e.g. α-glucosidase).
OBJECTIVE: Here we synthesize 10 chalcone derivatives to be evaluated their in vitro enzymatic inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
METHODS: The synthesis was carried out using Claissen-Schimdt condensation and the in vitro assay was conducted using Ellman Method.
RESULTS: Compounds 2b and 4b demonstrated as the best IC50 of 9.3 μM and 68.7 μM respectively, towards AChE and BChE inhibition. Molecular docking studies predicted that this activity might be due to the interaction of the chalcones with important amino acid residues in the binding site of AChE such as SER200 and in that of BChE, such as TRP82, SER198, TRP430, TYR440, LEU286 and VAL288.
CONCLUSION: Chalcone can be used as the scaffold for cholinesterase inhibitor, in particularly either fluorine or nitro group to be augmented at the para-position of Ring B, whereas the hydrophobic chain is necessary at the meta-position of Ring B.

Matched MeSH terms: Acetylcholinesterase/metabolism
Chemical composition and anticholinesterase inhibitory activity of the essential oil of Pseuduvaria macrophylla (Oliv.) Merr. from Malaysia

Salleh WMNHW, Khamis S, Nafiah MA, Abed SA

Nat Prod Res, 2021 Jun;35(11):1887-1892.
PMID: 31293176 DOI: 10.1080/14786419.2019.1639183

This study was designed to examine the chemical composition and anticholinesterase inhibitory activity of the essential oil of Pseuduvaria macrophylla (Oliv.) Merr. (Annonaceae) from Malaysia. The essential oil was obtained by hydrodistillation and fully analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The analysis led to the identification of thirty-four chemical components that represented 87.7 ± 0.5% of the total oil. The essential oil was found to be rich in germacrene D (21.1 ± 0.4%), bicyclogermacrene (10.5 ± 0.5%), δ-cadinene (5.6 ± 0.2%), α-copaene (5.1 ± 0.3%), and α-cadinol (5.0 ± 0.3%). Anticholinesterase activity was evaluated using Ellman method. The essential oil showed weak inhibitory activity against acetylcholinesterase (I%: 32.5%) and butyrylcholinesterase (I%: 35.4%) assays. Our findings demonstrate that the essential oil could be very useful for the characterization, pharmaceutical and therapeutic applications of the essential oil from Pseuduvaria macrophylla.

Matched MeSH terms: Acetylcholinesterase/metabolism
Fulltext Evaluation of difference in the neurotoxicity produced by dermal application of chlorpyrifos on the neonatal and adult mice

Mitra NK, Lee MS, Nadarajah VD

Trop Biomed, 2010 Apr;27(1):19-29.
PMID: 20562809

Dermal exposure to organophosphate pesticide is important because of its popular use. This study planned to compare the changes in serum acetylcholinesterase, paraoxonase and neuronal density of hippocampus and iso-cortex between two age groups of Swiss albino mice (18-day-old and 150-day-old) after dermal application of (1/2) LD50 of chlorpyrifos for 14 days. Statistically significant reduction was observed in serum acetylcholinesterase (Mann-Whitney test, p<0.05) and neuronal density (Independent samples t-test, p<0.05) in exposed groups compared to the control. The reduction in serum AChE and neuronal density was more pronounced in exposed adult mice than in exposed neonatal mice. The paraoxonase level was insignificant in control neonatal mice, whereas it was 890-fold more in exposed neonatal mice. Upregulated paraoxonase levels may be extrapolated to produce relatively lower reduction of cholinesterase and neuronal density in neonatal mice.

Matched MeSH terms: Acetylcholinesterase/metabolism
Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6

McGuire JR, Bester SM, Guelta MA, Cheung J, Langley C, Winemiller MD, et al.

Chem Res Toxicol, 2021 03 15;34(3):804-816.
PMID: 33538594 DOI: 10.1021/acs.chemrestox.0c00406

The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.

Matched MeSH terms: Acetylcholinesterase/metabolism*
Exploration of synthetic multifunctional amides as new therapeutic agents for Alzheimer's disease through enzyme inhibition, chemoinformatic properties, molecular docking and dynamic simulation insights

Hassan M, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Hussain G, Shah SAA, et al.

J Theor Biol, 2018 12 07;458:169-183.
PMID: 30243565 DOI: 10.1016/j.jtbi.2018.09.018

A new series of multifunctional amides has been synthesized having moderate enzyme inhibitory potentials and mild cytotoxicity. 2-Furyl(1-piperazinyl)methanone (1) was coupled with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) to form {4-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1-piperazinyl}(2-furyl)methanone (3). Different elecrophiles were synthesized by the reaction of various un/substituted anilines (4a-o) with 2-bromoacetylbromide (5), 2‑bromo‑N-(un/substituted-phenyl)acetamides (6a-o). Further, equimolar ratios of 3 and 6a-o were allowed to react in the presence of K2CO3 in acetonitrile to form desired multifunctional amides (7a-o). The structural confirmation of all the synthesized compounds was carried out by their EI-MS, IR, 1H NMR and 13C NMR spectral data. Enzyme inhibition activity was performed against acetyl and butyrylcholinestrase enzymes, whereby 7e showed very good activity having IC50 value of 5.54 ± 0.03 and 9.15 ± 0.01 μM, respectively, relative to eserine, a reference standard. Hemolytic activity of the molecules was checked to asertain their cytotoxicity towards red blood cell membrance and it was observed that most of the compounds were not toxic up to certain range. Moreover, chemoinformatic protepties and docking simulation results also showed the significance of 7e as compared to other compounds. Based on in vitro and in silico analysis 7e could be used as a template for the development of new drugs against Alzheimer's disease.

Matched MeSH terms: Acetylcholinesterase/metabolism
Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones

Parambi DGT, Aljoufi F, Murugaiyah V, Mathew GE, Dev S, Lakshminarayanan B, et al.

Cent Nerv Syst Agents Med Chem, 2019;19(1):67-71.
PMID: 30451121 DOI: 10.2174/1871524918666181119114016

BACKGROUND: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD).
METHODS: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated.
RESULTS: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively.
CONCLUSION: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

Matched MeSH terms: Acetylcholinesterase/metabolism

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