Displaying publications 1 - 20 of 79 in total

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  1. 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
  2. Fulltext N-Methyl Costaricine and Costaricine, Two Potent Butyrylcholinesterase Inhibitors from Alseodaphne pendulifolia Gamb
    Husna Hasnan MH, Sivasothy Y, Khaw KY, Nafiah MA, Hazni H, Litaudon M, et al.
    Int J Mol Sci, 2023 Jun 27;24(13).
    PMID: 37445877 DOI: 10.3390/ijms241310699
    Studies have been conducted over the last decade to identify secondary metabolites from plants, in particular those from the class of alkaloids, for the development of new anti-Alzheimer's disease (AD) drugs. The genus Alseodaphne, comprising a wide range of alkaloids, is a promising source for the discovery of new cholinesterase inhibitors, the first-line treatment for AD. With regard to this, a phytochemical investigation of the dichloromethane extract of the bark of A. pendulifolia Gamb. was conducted. Repeated column chromatography and preparative thin-layer chromatography led to the isolation of a new bisbenzylisoquinoline alkaloid, N-methyl costaricine (1), together with costaricine (2), hernagine (3), N-methyl hernagine (4), corydine (5), and oxohernagine (6). Their structures were elucidated by the 1D- and 2D-NMR techniques and LCMS-IT-TOF analysis. Compounds 1 and 2 were more-potent BChE inhibitors than galantamine with IC50 values of 3.51 ± 0.80 µM and 2.90 ± 0.56 µM, respectively. The Lineweaver-Burk plots of compounds 1 and 2 indicated they were mixed-mode inhibitors. Compounds 1 and 2 have the potential to be employed as lead compounds for the development of new drugs or medicinal supplements to treat AD.
    Matched MeSH terms: Acetylcholinesterase/metabolism
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Deep eutectic solvent mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and evaluation of biological activities targeting neurodegenerative disorders
    Saleem Khan M, Asif Nawaz M, Jalil S, Rashid F, Hameed A, Asari A, et al.
    Bioorg Chem, 2022 01;118:105457.
    PMID: 34798458 DOI: 10.1016/j.bioorg.2021.105457
    Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC50 = 0.31 ± 0.11 µM) and monoamine oxidase B (MAO B) (IC50 = 0.34 ± 0.04 µM) inhibitors respectively. All compounds were selective AChE inhibitors and did not inhibit BChE (<29% inhibition). Compound 1 k (IC50 = 0.13 ± 0.09 µM) was the most active AChE inhibitor.
    Matched MeSH terms: Acetylcholinesterase/metabolism*
  9. 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*
  10. Fulltext Analogues of 2'-hydroxychalcone with modified C4-substituents as the inhibitors against human acetylcholinesterase
    Sukumaran SD, Nasir SB, Tee JT, Buckle MJC, Othman R, Rahman NA, et al.
    J Enzyme Inhib Med Chem, 2021 Dec;36(1):130-137.
    PMID: 33243025 DOI: 10.1080/14756366.2020.1847100
    A series of C4-substituted tertiary nitrogen-bearing 2'-hydroxychalcones were designed and synthesised based on a previous mixed type acetylcholinesterase inhibitor. Majority of the 2'-hydroxychalcone analogues displayed a better inhibition against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 4c was identified as the most potent AChE inhibitor (IC50: 3.3 µM) and showed the highest selectivity for AChE over BuChE (ratio >30:1). Molecular docking studies suggested that compound 4c interacts with both the peripheral anionic site (PAS) and catalytic anionic site (CAS) regions of AChE. ADMET analysis confirmed the therapeutic potential of compound 4c based on its blood-brain barrier penetrating. Overall, the results suggest that this 2'-hydroxychalcone deserves further investigation into the therapeutic lead for Alzheimer's disease (AD).
    Matched MeSH terms: Acetylcholinesterase/metabolism*
  11. 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
  12. 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*
  13. New insights into the phytochemical composition, enzyme inhibition and antioxidant properties of desert cotton (Aerva javanica (Bum.f) Shult. -Amaranthaceae)
    Saleem H, Zengin G, Khan KU, Ahmad I, Waqas M, Mahomoodally FM, et al.
    Nat Prod Res, 2021 Feb;35(4):664-668.
    PMID: 30919661 DOI: 10.1080/14786419.2019.1587427
    This study sets out to probe into total bioactive contents, UHPLC-MS secondary metabolites profiling, antioxidant (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum and metal chelating) and enzyme inhibitory (acetylcholinesterase- AChE, butyrylcholinesterase- BChE, α-amylase, α glucosidase, and tyrosinase) activities of methanol extract of Aerva javanica, also known as desert cotton or Kapok bush. Aerva javanica contains considerable phenolic (44.79 ± 3.12 mg GAE/g) and flavonoid (28.86 ± 0.12 mg QE/g) contents which tends to correlate with its significant antioxidant potential for ABTS, FRAP and CUPRAC assays with values of 101.41 ± 1.18, 124.10 ± 1.71 and 190.22 ± 5.70 mg TE/g, respectively. The UHPLC-MS analysis identified the presence of 45 phytochemicals belonging to six major groups: phenolic, flavonoids, lignin, terpenes, glycoside and alkaloid. Moreover, the plant extract also showed potent inhibitory action against AChE (3.73 ± 0.22 mg GALAE/g), BChE (3.31 ± 0.19 mg GALAE/g) and tyrosinase (126.05 ± 1.77 mg KAE/g). The observed results suggest A. javanica could be further explored as a natural source of bioactive compounds.
    Matched MeSH terms: Acetylcholinesterase/metabolism
  14. Probing 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones as multi-target directed ligands against cholinesterases, carbonic anhydrases and α-glycosidase enzymes
    Hashmi S, Khan S, Shafiq Z, Taslimi P, Ishaq M, Sadeghian N, et al.
    Bioorg Chem, 2021 02;107:104554.
    PMID: 33383322 DOI: 10.1016/j.bioorg.2020.104554
    With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease.
    Matched MeSH terms: Acetylcholinesterase/metabolism
  15. In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids
    Mohd Faudzi SM, Leong SW, Auwal FA, Abas F, Wai LK, Ahmad S, et al.
    Arch Pharm (Weinheim), 2021 Jan;354(1):e2000161.
    PMID: 32886410 DOI: 10.1002/ardp.202000161
    A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.
    Matched MeSH terms: Acetylcholinesterase/metabolism
  16. 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
  17. 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
  18. New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer's treatment: In silico identification, in vitro and in vivo validation
    Anwar F, Saleem U, Ahmad B, Ashraf M, Rehman AU, Froeyen M, et al.
    Comput Biol Chem, 2020 Dec;89:107378.
    PMID: 33002716 DOI: 10.1016/j.compbiolchem.2020.107378
    Neurodegenerative diseases have complex etiology and pose a challenge to scientists to develop simple and cost-effective synthetic compounds as potential drug candidates for such diseases. Here, we report an extension of our previously published in silico screening, where we selected four new compounds as AChE inhibitors. Further, based on favorable binding possess, MD simulation and MMGBSA, two most promising compounds (3a and 3b) were selected, keeping in view the ease of synthesis and cost-effectiveness. Due to the critical role of BChE, LOX and α-glucosidase in neurodegeneration, the selected compounds were also screened against these enzymes. The IC50 values of 3a against AChE and BChE found to be 12.53 and 352.42 μM, respectively. Moderate to slight inhibitions of 45.26 % and 28.68 % were presented by 3a against LOX and α-glucosidase, respectively, at 0.5 mM. Insignificant inhibitions were observed with 3b against the four selected enzymes. Further, in vivo trial demonstrated that 3a could significantly diminish AChE levels in the mice brain as compared to the control. These findings were in agreement with the histopathological analysis of the brain tissues. The results corroborate that selected compounds could serve as a potential lead for further development and optimization as AChE inhibitors to achieve cost-effective anti-Alzheimer's drugs.
    Matched MeSH terms: Acetylcholinesterase/metabolism*
  19. Fulltext LC-QTOF-MS analysis of xanthone content in different parts of Garcinia mangostana and its influence on cholinesterase inhibition
    Khaw KY, Chong CW, Murugaiyah V
    J Enzyme Inhib Med Chem, 2020 Dec;35(1):1433-1441.
    PMID: 32608273 DOI: 10.1080/14756366.2020.1786819
    Mangosteen is one of the best tasting tropical fruit widely cultivated in Southeast Asia. This study aimed to quantify xanthone content in different parts of Garcinia mangostana by LC-QTOF-MS and determine its influence on their cholinesterase inhibitory activities. The total xanthone content in G. mangostana was in the following order: pericarp > calyx > bark > stalk > stem > leaves > aril. The total xanthone content of pericarp was 100 times higher than the aril. Methanol extracts of the pericarp and calyx demonstrated the most potent inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 0.90 and 0.37 µg/mL, respectively. Statistical analysis showed a strong correlation between xanthone content and cholinesterase inhibition. Nonmetric multidimensional scaling analysis revealed α-mangostin and γ-mangostin of pericarp as the key metabolites contributing to cholinesterase inhibition. Due to the increasing demand of mangosteen products, repurposing of fruit waste (pericarp) has great potential for enhancement of the cognitive health of human beings.
    Matched MeSH terms: Acetylcholinesterase/metabolism
  20. Probing simple structural modification of α-mangostin on its cholinesterase inhibition and cytotoxicity
    Khaw KY, Kumar P, Yusof SR, Ramanathan S, Murugaiyah V
    Arch Pharm (Weinheim), 2020 Nov;353(11):e2000156.
    PMID: 32716578 DOI: 10.1002/ardp.202000156
    α-Mangostin has been reported to possess a broad range of pharmacological effects including potent cholinesterase inhibition, but the development of α-mangostin as a potential lead compound is impeded by its toxicity. The present study investigated the impact of simple structural modification of α-mangostin on its cholinesterase inhibitory activities and toxicity toward neuroblastoma and liver cancer cells. The dialkylated derivatives retained good acetylcholinesterase (AChE) inhibitory activities with IC50 values between 4.15 and 6.73 µM, but not butyrylcholinesterase (BChE) inhibitory activities, compared with α-mangostin, a dual inhibitor (IC50 : AChE, 2.48 µM; BChE, 5.87 µM). Dialkylation of α-mangostin produced AChE selective inhibitors that formed hydrophobic interactions at the active site of AChE. Interestingly, all four dialkylated derivatives of α-mangostin showed much lower cytotoxicity, being 6.4- to 9.0-fold and 3.8- to 5.5-fold less toxic than their parent compound on neuroblastoma and liver cancer cells, respectively. Likewise, their selectivity index was higher by 1.9- to 4.4-fold; in particular, A2 and A4 showed improved selectivity index compared with α-mangostin. Taken together, modification of the hydroxyl groups of α-mangostin at positions C-3 and C-6 greatly influenced its BChE inhibitory and cytotoxic but not its AChE inhibitory activities. These dialkylated derivatives are viable candidates for further structural modification and refinement, worthy in the search of new AChE inhibitors with higher safety margins.
    Matched MeSH terms: Acetylcholinesterase/metabolism*
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