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Fulltext Assay for heavy metals using an inhibitive assay based on the acetylcholinesterase from Clarias batrachus

Abubakar M. Umar, Tham, Lik Gin, Natarajan Perumal, Nur Adeela Yasid, Hassan Mohd Daud, Mohd Yunus Shukor

Bioremediation Science and Technology Research, 2016;4(2):6-10.
MyJurnal

Acetylcholinesterase (AChE) is usually used as an inhibitive assay for insecticides. A lesserknown
property of AChE is its inhibition by heavy metals. In this work, we evaluate an AChE
from brains of Clarias batrachus (catfish) exposed to wastes from aquaculture industry as an
inhibitive assay for heavy metals. We discovered that the AChE was inhibited completely by
Hg2+, Ag2+, Pb2+, Cu2+, Cd2+, Cr6+ and Zn2+ during initial screening. When tested at various
concentrations, the heavy metals exhibited exponential decay type inhibition curves. The
calculated IC50 (mg/L) for the heavy metals Ag2+, Cu2+, Hg2+, Cr6+ and Cd2+ were 0.088, 0.078,
0.071, 0.87 and 0.913, respectively. The IC50 for these heavy metals are comparable, and some
are lower than the IC50 values from the cholinesterases from previously studied fish. The assay
can be carried out in less than 30 minutes at ambient temperature.

Matched MeSH terms: Acetylcholinesterase
Fulltext Polystyrene Microplastics Exposure: An Insight into Multiple Organ Histological Alterations, Oxidative Stress and Neurotoxicity in Javanese Medaka Fish (Oryzias javanicus Bleeker, 1854)

Usman S, Abdull Razis AF, Shaari K, Amal MNA, Saad MZ, Mat Isa N, et al.

Int J Environ Res Public Health, 2021 09 07;18(18).
PMID: 34574375 DOI: 10.3390/ijerph18189449

Microplastics (MPs) have become pollutants of concern due to their unknown human health effect and negative impact on terrestrial and aquatic ecosystems. There is increasing number of experimental research on MPs globally with its effects not fully understood; recent animal studies explore its effects on the intestines, yet on other vital organs. Javanese medaka fish was exposed to polystyrene microplastics (PS-MPs) beads for a period of 21 days. Histological alterations, intestinal oxidative stress, permeability and neurotoxicity were evaluated. Significant inflammatory changes and tissue damage were observed in the intestine, liver and kidney. Intestinal oxidative stress and permeability were found to be significantly increased. In the brain, neurotoxicity characterised by a significant induction of oxidative stress, lipid peroxidation and the inhibition of acetylcholinesterase enzyme were elucidated. This study provided an insight into the multiple organ effect of microplastics exposure, necessitating further exploration and identification of biomarkers to be utilised for biomonitoring population at risk in the future.

Matched MeSH terms: Acetylcholinesterase
Potential biomarker of phenol toxicity in freshwater fish C. mrigala: Serum cortisol, enzyme acetylcholine esterase and survival organ gill

Muthukumaravel K, Kanagavalli V, Pradhoshini KP, Vasanthi N, Santhanabharathi B, Alam L, et al.

Comp Biochem Physiol C Toxicol Pharmacol, 2023 Jan;263:109492.
PMID: 36283648 DOI: 10.1016/j.cbpc.2022.109492

In this modern industrialized era of large-scale production of agrochemicals, various emerging contaminants form the main components of waste water and sludge in most of the developing countries of the world. In this concern, phenol- an inevitable and alarming chemical pollutant in aquatic ecosystem, gains a speedy access into the water bodies as an industrial by-product. Though the detrimental effects of phenol have been studied in various aspects of aquatic life, current study is an initiative to unravel the toxic effects of phenol at molecular level in Cirrhinus mrigala. Plasma cortisol level and acetylcholine esterase activity in fish was estimated by Chemiluminescent immunoassay technique and Ellman assay respectively. Scanning electron microscopic studies were carried out to unravel the gill histopathological alterations in exposed fish. It was observed that phenol (22.32 mg/l) inhibits 50 % of acetylcholine esterase activity in brain thereby affecting the locomotion of the targeted carp. Cortisol elevated during the 7th day in exposed fish, but declined progressively on the forthcoming 21st and 28th days. Manifestations in gill encompass curling, fusion, aberrations, sloughing of gill epithelium, wider inter filamentary space and mucus coating in the primary gill filament. It concludes that the discernable deviations produced in both biochemical parameters and key organ gill can be used as a biomarker and bio-indicator respectively for assessing the existence of emerging toxicants in aquatic ecosystem.

Matched MeSH terms: Acetylcholinesterase
Fulltext Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity

Chear NJ, Khaw KY, Murugaiyah V, Lai CS

J Food Drug Anal, 2016 04;24(2):358-366.
PMID: 28911590 DOI: 10.1016/j.jfda.2015.12.005

Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer's disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences.

Matched MeSH terms: Acetylcholinesterase
Fulltext Evaluation of bioactive compounds from Ficus carica L. leaf extracts via high-performance thin-layer chromatography combined with effect-directed analysis

Agatonovic-Kustrin S, Wong S, Dolzhenko AV, Gegechkori V, Ku H, Tucci J, et al.

J Chromatogr A, 2023 Sep 13;1706:464241.
PMID: 37541060 DOI: 10.1016/j.chroma.2023.464241

This study compares different solvent systems with the use of spontaneous fermentation on the phytochemical composition of leaf extracts from a locally grown white variety of common fig (Ficus carica Linn.). The aim was to detect and identify bioactive compounds that are responsible for acetylcholinesterase (AChE), α-amylase and cyclooxygenase-1 (COX-1) enzyme inhibition, and compounds that exhibit antimicrobial activity. Bioactive zones in chromatograms were detected by combining High-performance thin-layer chromatography (HPTLC) with enzymatic and biological assays. A new experimental protocol for measuring the relative half-maximum inhibitory concentration (IC50) was designed to evaluate the potency of the extracts compared to the potency of known inhibitors. Although the IC50 of the fig leaf extract for α-amylase and AChE inhibition were significantly higher when compared to IC50 for acarbose and donepezil, the COX-1 inhibition by the extract (IC50 = 627 µg) was comparable to that of salicylic acid (IC50 = 557 µg), and antimicrobial activity of the extract (IC50 = 375-511 µg) was similar to ampicillin (IC50 = 495 µg). Four chromatographic zones exhibited bioactivity. Compounds from detected bioactive bands were provisionally identified by comparing the band positions to coeluted standards, and by Fourier transform infrared (FTIR) spectra from eluted zones. Flash chromatography was used to separate selected extract into fractions and isolate fractions that are rich in bioactive compounds for further characterisation with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) analysis. The main constituents identified were umbelliferon (zone 1), furocoumarins psoralen and bergapten (zone 2), different fatty acids (zone 3 and 4), and pentacyclic triterpenoids (calotropenyl acetate or lupeol) and stigmasterol (zone 4).

Matched MeSH terms: Acetylcholinesterase
Essential oils composition of Litsea glauca and Litsea fulva and their anticholinesterase inhibitory activity

Salleh WMNHW, Salihu AS, Ab Ghani N

Nat Prod Res, 2024;38(4):629-633.
PMID: 36794425 DOI: 10.1080/14786419.2023.2180507

This study was designed to examine the essential oils compositions of Litsea glauca Siebold and Litsea fulva Fern.-Vill. growing in Malaysia. The essential oils were achieved by hydrodistillation and fully characterized by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The study identified 17 and 19 components from the leaf oils from L. glauca (80.7%) and L. fulva (81.5%), respectively. The major components of L. glauca oil were β-selinene (30.8%), β-calacorene (11.3%), tridecanal (7.6%), isophytol (4.8%) and β-eudesmol (4.5%); whereas in L. fulva oil gave β-caryophyllene (27.8%), caryophyllene oxide (12.8%), α-cadinol (6.3%), (E)-nerolidol (5.7%), β-selinene (5.5%) and tridecanal (5.0%). Anticholinesterase activity was evaluated using Ellman method. The essential oils showed moderate inhibitory activity on acetylcholinesterase and butyrylcholinesterase assays. Our findings demonstrate that the essential oil could be very useful for the characterization, pharmaceutical, and therapeutic applications of the essential oil from the genus Litsea.

Matched MeSH terms: Acetylcholinesterase
Fulltext Unveiling the Antioxidant, Clinical Enzyme Inhibitory Properties and Cytotoxic Potential of Tambourissa peltata Baker-An Understudied Endemic Plant

Suroowan S, Llorent-Martínez EJ, Zengin G, Buskaran K, Fakurazi S, Abdalla AN, et al.

Molecules, 2023 Jan 06;28(2).
PMID: 36677655 DOI: 10.3390/molecules28020599

This study documents for the first time the phytochemical composition and biological activities of Tambourissa peltata Baker, an endemic plant from Mauritius. Phytochemical extraction was performed using ethyl acetate, methanol and distilled water as solvents. The phytochemical composition was determined through HPLC-MS and other standard assays. The DPPH, ABTS, FRAP, CUPRAC and phosphomolybdenum assays were employed for the determination of the antioxidant potential, whereas cell viability assays were used to determine the cytotoxicity. The highest phenolic and phenolic acid contents were obtained in the aqueous extract (179.91 ± 0.67 gallic acid equivalents/g and 55.74 ± 1.43 caffeic acid equivalents/g). The highest quantity of flavonoids was obtained in the ethyl acetate extract (28.97 ± 0.46 rutin equivalents/g). The methanolic extract was the highest source of flavonols (33.71 ± 0.13 mg catechin equivalents/g). A total of 34 phytochemicals were identified, mainly proanthocyanidins and flavonoid glycosides. The highest antioxidant activity in DPPH (973.40 ± 5.65 mg TE (Trolox equivalents)/g), ABTS (2030.37 ± 40.83 mg TE/g), FRAP (1461.39 ± 5.95 mg TE/g), CUPRAC (1940.99 ± 20.95 mg TE/g) and phosphomolybdenum (8.37 ± 0.23 mmol TE/g) assays was recorded for the aqueous extract. The ethyl acetate extract was the most active metal chelator. The highest acetylcholinesterase inhibitor was the methanolic extract, whereas the ethyl acetate extract was the most active against BChE. The tyrosinase enzyme was most inhibited by the methanolic extract. Alpha-amylase and glucosidase were most inhibited by the aqueous extract. The methanolic extract was capable of inducing cell cytotoxicity to the human colorectal carcinoma without damaging normal cells. T. peltata warrants further attention from the scientific community given its multifaceted biological properties.

Matched MeSH terms: Acetylcholinesterase
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*
Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives

Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Ali MA

Bioorg Med Chem, 2013 Jun 1;21(11):3022-31.
PMID: 23602518 DOI: 10.1016/j.bmc.2013.03.058

A series of hitherto unreported pyrido-pyrimidine-2-ones/pyrimidine-2-thiones were synthesized under microwave assisted solvent free reaction conditions in excellent yields and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Among the pyridopyrimidine derivatives, 7e and 7l displayed 2.5- and 1.5-fold higher enzyme inhibitory activities against AChE as compared to standard drug, galanthamine, with IC50 of 0.80 and 1.37 μM, respectively. Interestingly, all the compounds except 6k, 7j and 7k displayed higher inhibitory potential against BChE enzyme in comparison to standard with IC50 ranging from 1.18 to 18.90 μM. Molecular modeling simulations of 7e and 7l was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) and human butyrylcholinesterase (hBChE) enzymes to disclose binding interaction and orientation of these molecule into the active site gorge of respective receptors.

Matched MeSH terms: Acetylcholinesterase/chemistry*
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
Fulltext Potential Anti-Acetylcholinesterase Activity of Cassia timorensis DC

Azman NAN, Alhawarri MB, Rawa MSA, Dianita R, Gazzali AM, Nogawa T, et al.

Molecules, 2020 Oct 04;25(19).
PMID: 33020403 DOI: 10.3390/molecules25194545

Seventeen methanol extracts from different plant parts of five different Cassia species, including C. timorensis, C. grandis, C. fistula, C. spectabilis, and C. alata were screened against acetylcholinesterase (AChE). C. timorensis extracts were found to exhibit the highest inhibition towards AChE whereby the leaf, stem, and flower methanol extracts showed 94-97% inhibition. As far as we are aware, C. timorensis is one of the least explored Cassia spp. for bioactivity. Further fractionation led to the identification of six compounds, isolated for the first time from C. timorensis: 3-methoxyquercetin (1), benzenepropanoic acid (2), 9,12,15-octadecatrienoic acid (3), β-sitosterol (4), stigmasterol (5), and 1-octadecanol (6). Compound 1 showed moderate inhibition towards AChE (IC50: 83.71 μM), while the other compounds exhibited poor to slightly moderate AChE inhibitory activity. Molecular docking revealed that the methoxy substitution of 1 formed a hydrogen bond with TYR121 at the peripheral anionic site (PAS) and the hydroxyl group at C5 formed a covalent hydrogen bond with ASP72. Additionally, the OH group at the C3' position formed an interaction with the protein at the acyl pocket (PHE288). This possibly explains the activity of 1 in blocking the entry of acetylcholine (ACh, the neurotransmitter), thus impeding the hydrolysis of ACh.

Matched MeSH terms: Acetylcholinesterase/chemistry*
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 Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies

Kwong HC, Mah SH, Chia TS, Quah CK, Lim GK, Kumar CSC

Molecules, 2017 Jun 17;22(6).
PMID: 28629119 DOI: 10.3390/molecules22061005

Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives with various substituents on the phenyl ring using Ellman's colorimetric method. Compound 2e with a 2,4-dichloro electron-withdrawing substituent on the phenyl ring exhibited the strongest inhibition effect against AChE, with an IC50 value of 77.15 µM. Overall, the adamantyl-based ester with the mono-substituent at position 3 of the phenyl ring exhibited good AChE inhibition effects with an ascending order for the substituents: Cl < NO₂ < CH₃ < OCH₃. Furthermore, compounds with electron-withdrawing groups (Cl and NO₂) substituted at position 3 on their phenyl rings demonstrated stronger AChE inhibition effects, in comparison to their respective positional isomers. On the other hand, compound 2j with a 3-methoxyphenyl ring showed the highest inhibition effect against BChE, with an IC50 value of 223.30 µM. Molecular docking analyses were conducted for potential AChE and BChE inhibitors, and the results demonstrated that the peripheral anionic sites of target proteins were predominant binding sites for these compounds through hydrogen bonds and halogen interactions instead of hydrophobic interactions in the catalytic active site.

Matched MeSH terms: Acetylcholinesterase/chemistry*
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
Fulltext Multitargeted Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Rosmarinus officinalis against Alzheimer's Disease

Mirza FJ, Zahid S, Amber S, Sumera, Jabeen H, Asim N, et al.

Molecules, 2022 Oct 25;27(21).
PMID: 36364071 DOI: 10.3390/molecules27217241

Alzheimer's disease (AD) has been associated with the hallmark features of cholinergic dysfunction, amyloid beta (Aβ) aggregation and impaired synaptic transmission, which makes the associated proteins, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE I), acetylcholine esterase (AChE) and synapsin I, II and III, major targets for therapeutic intervention. The present study investigated the therapeutic potential of three major phytochemicals of Rosmarinus officinalis, ursolic acid (UA), rosmarinic acid (RA) and carnosic acid (CA), based on their binding affinity with AD-associated proteins. Detailed docking studies were conducted using AutoDock vina followed by molecular dynamic (MD) simulations using Amber 20. The docking analysis of the selected molecules showed the binding energies of their interaction with the target proteins, while MD simulations comprising root mean square deviation (RMSD), root mean square fluctuation (RMSF) and molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations were carried out to check the stability of bound complexes. The drug likeness and the pharmacokinetic properties of the selected molecules were also checked through the Lipinski filter and ADMETSAR analysis. All these bioactive compounds demonstrated strong binding affinity with AChE, BACE1 and synapsin I, II and III. The results showed UA and RA to be potential inhibitors of AChE and BACE1, exhibiting binding energies comparable to those of donepezil, used as a positive control. The drug likeness and pharmacokinetic properties of these compounds also demonstrated drug-like characteristics, indicating the need for further in vitro and in vivo investigations to ascertain their therapeutic potential for AD.

Matched MeSH terms: Acetylcholinesterase/metabolism
Xanthone: Potential Acetylcholinesterase Inhibitor for Alzheimer's Disease Treatment

Vanessa VV, Mah SH

Mini Rev Med Chem, 2021;21(17):2507-2529.
PMID: 33583373 DOI: 10.2174/1389557521666210212152514

Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible central nervous system impairment, which has become one of the severe issues recently. The most successful approach of Alzheimer's treatment is the administration of cholinesterase inhibitors to prevent the hydrolysis of acetylcholine and subsequently improve cholinergic postsynaptic transmission. This review highlights a class of heterocycles, namely xanthone, and its remarkable acetylcholinesterase inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano, and glycosylated xanthones, exhibited promising inhibition effects towards acetylcholinesterase. Interestingly, synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine, and morpholine have shown greater acetylcholinesterase inhibition activities. The structure-activity relationship of xanthones revealed that the type and position of the substituent(s) attached to the xanthone moiety influenced acetylcholinesterase inhibition activities where hydrophobic moiety will lead to an improved activity by contributing to the π-π interactions, as well as the hydroxy substituent(s) by forming hydrogen-bond interactions. Thus, further studies, including quantitative structure-activity relationship, in vivo and clinical validation studies are crucial for the development of xanthones into novel anti-Alzheimer's disease drugs.

Matched MeSH terms: Acetylcholinesterase/metabolism
Fulltext New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors

Loh ZH, Kwong HC, Lam KW, Teh SS, Ee GCL, Quah CK, et al.

J Enzyme Inhib Med Chem, 2021 Dec;36(1):627-639.
PMID: 33557647 DOI: 10.1080/14756366.2021.1882452

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.

Matched MeSH terms: Acetylcholinesterase/metabolism*

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