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  1. Fulltext Synthesis of Benzimidazole-Based Analogs as Anti Alzheimer's Disease Compounds and Their Molecular Docking Studies
    Adalat B, Rahim F, Taha M, Alshamrani FJ, Anouar EH, Uddin N, et al.
    Molecules, 2020 Oct 20;25(20).
    PMID: 33092223 DOI: 10.3390/molecules25204828
    We synthesized 10 analogs of benzimidazole-based thiosemicarbazide 1 (a-j) and 13 benzimidazole-based Schiff bases 2 (a-m), and characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibition activities. All the synthesized analogs showed varying degrees of acetylcholinesterase and butyrylcholinesterase inhibitory potentials in comparison to the standard drug (IC50 = 0.016 and 4.5 µM. Amongst these analogs 1 (a-j), compounds 1b, 1c, and 1g having IC50 values 1.30, 0.60, and 2.40 µM, respectively, showed good acetylcholinesterase inhibition when compared with the standard. These compounds also showed moderate butyrylcholinesterase inhibition having IC50 values of 2.40, 1.50, and 2.40 µM, respectively. The rest of the compounds of this series also showed moderate to weak inhibition. While amongst the second series of analogs 2 (a-m), compounds 2c, 2e, and 2h having IC50 values of 1.50, 0.60, and 0.90 µM, respectively, showed moderate acetylcholinesterase inhibition when compared to donepezil. Structure Aactivity Relation of both synthesized series has been carried out. The binding interactions between the synthesized analogs and the enzymes were identified through molecular docking simulations.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  2. 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: Cholinesterase Inhibitors/chemistry
  3. Fulltext The antiacetylcholinesterase and antileishmanial activities of Canarium patentinervium Miq
    Mogana R, Adhikari A, Debnath S, Hazra S, Hazra B, Teng-Jin K, et al.
    Biomed Res Int, 2014;2014:903529.
    PMID: 24949478 DOI: 10.1155/2014/903529
    In continuation of our natural and medicinal research programme on tropical rainforest plants, a bioassay guided fractionation of ethanolic extract of leaves of Canarium patentinervium Miq. (Burseraceae Kunth.) led to the isolation of scopoletin (1), scoparone (2), (+)-catechin (3), vomifoliol (4), lioxin (5), and syringic acid (6). All the compounds exhibited antiacetylcholinesterase activity with syringic acid, a phenolic acid exhibiting good AChE inhibition (IC50 29.53 ± 0.19 μ g/mL). All compounds displayed moderate antileishmanial activity with scopoletin having the highest antileishmanial activity (IC50 163.30 ± 0.32 μ g/mL). Given the aforementioned evidence, it is tempting to speculate that Canarium patentinervium Miq. represents an exciting scaffold from which to develop leads for treatment of neurodegenerative and parasitic diseases.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  4. Anti-cholinesterase potential of diverse botanical families from Malaysia: Evaluation of crude extracts and fractions from liquid-liquid extraction and acid-base fractionation
    Amir Rawa MS, Hassan Z, Murugaiyah V, Nogawa T, Wahab HA
    J Ethnopharmacol, 2019 Dec 05;245:112160.
    PMID: 31419500 DOI: 10.1016/j.jep.2019.112160
    ETHNOPHARMACOLOGICAL RELEVANCE: Enhancement of cholinergic functions in the brain via acetylcholinesterase inhibition is one of the main therapeutic strategies to improve symptoms associated with Alzheimer's or related cognitive deficits. There is a pathophysiological correlation between Alzheimer's and Diabetes Mellitus, as well as inflammation and oxidative stress that may cause cognitive decline.

    AIM OF THE STUDY: The present study was intended to evaluate anti-cholinesterase potential of 177 Malaysian plant extracts from 148 species known to have related ethnomedicinal uses such as anti-inflammatory, anti-oxidant, anti-diabetic, epilepsy, headache, memory enhancement and anti-aging.

    MATERIALS AND METHODS: Anti-cholinesterase screening against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes was performed on the basis of in-vitro colorimetric 96-well microplate-based assay method. Potent active plant extracts were subjected to liquid-liquid extraction and acid-base fractionation for further analysis.

    RESULTS: Fifty-seven plant extracts exhibited potent anti-cholinesterase activities (50-100% inhibition) at 200 μg/ml. Majority of the active plants originated from Fabaceae family. Coccoloba uvifera (L.) L. stem extract manifested the lowest IC50 of 3.78 μg/ml for AChE and 5.94 μg/ml for BChE. A few native species including Tetracera indica (Christm. & Panz.) Merr., Cyrtostachys renda Blume and Ixora javanica (Blume) DC. showed cholinesterase inhibition despite limited local medical applications. Further anti-AChE evaluation (50 μg/ml) of 18 potent plant extracts harbored active polar components in butanol and water fractions, except Senna pendula (Willd.) H.S.Irwin & Barneby (leaves and stems), Acacia auriculiformis Benth. (leaves), Artocarpus altilis (Parkinson ex F.A.Zorn) Fosberg (leaves), and Macaranga tanarius (L.) Mull.Arg. (leaves) that showed inhibitory activity in less polar fractions. The acidic extraction of these four plant species improved their inhibition level against AChE.

    CONCLUSION: This study rendered a preliminary overview of anti-cholinesterase activity from diverse Malaysian botanical families in which provided the medical relevance toward these native plant species, especially ones with limited ethnobotanical record or practice.

    Matched MeSH terms: Cholinesterase Inhibitors/chemistry*
  5. 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: Cholinesterase Inhibitors/chemistry*
  6. Fulltext Antioxidant, Anti-Inflammatory, and Inhibition of Acetylcholinesterase Potentials of Cassia timoriensis DC. Flowers
    Alhawarri MB, Dianita R, Razak KNA, Mohamad S, Nogawa T, Wahab HA
    Molecules, 2021 Apr 29;26(9).
    PMID: 33946788 DOI: 10.3390/molecules26092594
    Despite being widely used traditionally as a general tonic, especially in South East Asia, scientific research on Cassia timoriensis, remains scarce. In this study, the aim was to evaluate the in vitro activities for acetylcholinesterase (AChE) inhibitory potential, radical scavenging ability, and the anti-inflammatory properties of different extracts of C. timoriensis flowers using Ellman's assay, a DPPH assay, and an albumin denaturation assay, respectively. With the exception of the acetylcholinesterase activity, to the best of our knowledge, these activities were reported for the first time for C. timoriensis flowers. The phytochemical analysis confirmed the existence of tannins, flavonoids, saponins, terpenoids, and steroids in the C. timoriensis flower extracts. The ethyl acetate extract possessed the highest phenolic and flavonoid contents (527.43 ± 5.83 mg GAE/g DW and 851.83 ± 10.08 mg QE/g DW, respectively) as compared to the other extracts. In addition, the ethyl acetate and methanol extracts exhibited the highest antioxidant (IC50 20.12 ± 0.12 and 34.48 ± 0.07 µg/mL, respectively), anti-inflammatory (92.50 ± 1.38 and 92.22 ± 1.09, respectively), and anti-AChE (IC50 6.91 ± 0.38 and 6.40 ± 0.27 µg/mL, respectively) activities. These results suggest that ethyl acetate and methanol extracts may contain bioactive compounds that can control neurodegenerative disorders, including Alzheimer's disease, through high antioxidant, anti-inflammatory, and anti-AChE activities.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  7. 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: Cholinesterase Inhibitors/chemistry*
  8. New cholinesterase inhibitors from Garcinia atroviridis
    Tan WN, Khairuddean M, Wong KC, Khaw KY, Vikneswaran M
    Fitoterapia, 2014 Sep;97:261-7.
    PMID: 24924287 DOI: 10.1016/j.fitote.2014.06.003
    A triflavanone, Garcineflavanone A (1) and a biflavonol, Garcineflavonol A (2) have been isolated from the stem bark of Garcinia atroviridis (Clusiaceae), collected in Peninsular Malaysia. Their structures were established using one and two-dimensional NMR, UV, IR and mass spectrometry and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Molecular docking studies of the isolated compounds were performed using docking procedure of AutoDock to disclose the binding interaction and orientation of these molecules into the active site gorge.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  9. 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: Cholinesterase Inhibitors/chemistry
  10. Ethyl nitrobenzoate: A novel scaffold for cholinesterase inhibition
    Yeong KY, Liew WL, Murugaiyah V, Ang CW, Osman H, Tan SC
    Bioorg Chem, 2017 02;70:27-33.
    PMID: 27863748 DOI: 10.1016/j.bioorg.2016.11.005
    A series of novel cholinesterase inhibitors containing nitrobenzoate core structure were synthesized by a facile and efficient method. The structure of the novel compounds were fully characterized and confirmed by analytical as well as spectroscopic methods. Compound indicated as 2f was found to possess the best cholinesterase inhibitory activities of all the evaluated compounds. Results suggest that 2f is a selective acetylcholinesterase inhibitor, although it also inhibits butyrylcholinesterase at higher concentration. Kinetics inhibition result suggest that 2f is a mixed-mode inhibitor of acetylcholinesterase. In addition, it was found to have low cytotoxicity. Molecular docking on compound 2f was carried out to rationalize the observed in vitro enzymatic assay results. Most importantly, the potential of nitrobenzoate derivatives as cholinesterase inhibitor was shown through this study. In summary, we discovered nitrobenzoates as a new scaffold that may eventually yield useful compounds in treatment of Alzheimer's disease.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry*
  11. Tyrosinase inhibition, anti-acetylcholinesterase, and antimicrobial activities of the phytochemicals from Gynotroches axillaris Blume
    Abed SA, Sirat HM, Taher M
    Pak J Pharm Sci, 2016 Nov;29(6):2071-2078.
    PMID: 28375126
    The leaves of Gynotroches axillaris were chemically and biologically studied. Sequential extraction of the leaves using petroleum ether, chloroform, and methanol afforded three extracts. Purification of pet. ether extract yielded, squalene and β-amyrin palmitate as the major compounds, together with palmitic acid and myristic acid as the minor components. The methanol extract yielded two flavonoids, quercitrin and epicatechin. The isolated compounds were characterized by MS, IR and NMR (1D and 2D). Anti-acetyl cholinesterase screening using TLC bio-autography assay showed that palmitic acid and myristic acid were the strongest inhibition with detection limit 1.14 and 1.28 μ/g/ 5 μL respectively. Antibacterial against Gram-positive and negative and antifungal activities exhibited that β-amyrin palmitate was the strongest (450-225 μ/mL) against all the tested microbes. The tyrosinase inhibition assay of extracts and the pure compounds were screened against tyrosinase enzyme. The inhibition percentage (I%) of methanol extract against tyrosinase enzyme was stronger than the other extracts with value 68.4%. Quercitrin (59%) was found to be the highest in the tyrosinase inhibition activity amongst the pure compounds. To the best of our knowledge, this is first report on the phytochemicals, tyrosinase inhibition, anti-acetycholinesterase and antimicrobial activities of the leaves of G. axillaris.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  12. Medroxyprogesterone derivatives from microbial transformation as anti-proliferative agents and acetylcholineterase inhibitors (combined in vitro and in silico approaches)
    Yusop SNW, Imran S, Adenan MI, Sultan S
    Steroids, 2020 12;164:108735.
    PMID: 32976918 DOI: 10.1016/j.steroids.2020.108735
    The fungal transformations of medroxyrogesterone (1) were investigated for the first time using Cunninghamella elegans, Trichothecium roseum, and Mucor plumbeus. The metabolites obtained are as following: 6β, 20-dihydroxymedroxyprogesterone (2), 12β-hydroxymedroxyprogesterone (3), 6β, 11β-dihydroxymedroxyprogesterone (4), 16β-hydroxymedroxyprogesterone (5), 11α, 17-dihydroxy-6α-methylpregn-4-ene-3, 20-dione (6), 11-oxo-medroxyprogesterone (7), 6α-methyl-17α-hydroxypregn-1,4-diene-3,20-dione (8), and 6β-hydroxymedroxyprogesterone (9), 15β-hydroxymedroxyprogesterone (10), 6α-methyl-17α, 11β-dihydroxy-5α-pregnan-3, 20-dione (11), 11β-hydroxymedroxyprogesterone (12), and 11α, 20-dihydroxymedroxyprogesterone (13). Among all the microbial transformed products, the newly isolated biotransformed product 13 showed the most potent activity against proliferation of SH-SY5Y cells. Compounds 12, 5, 6, 9, 11, and 3 (in descending order of activity) also showed some extent of activity against SH-SY5Y tumour cell line. The never been reported biotransformed product, 2, showed the most potent inhibitory activity against acetylcholinesterase. Molecular modelling studies were carried out to understand the observed experimental activities, and also to obtain more information on the binding mode and the interactions between the biotransformed products, and enzyme.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  13. Assessment of Clarias batrachus as a source of acetylcholinesterase (AchE) for the detection of insecticides
    Tham LG, Perumal N, Syed MA, Shamaan NA, Shukor MY
    J Environ Biol, 2009 Jan;30(1):135-8.
    PMID: 20112875
    An inhibitive assay of insecticides using Acetylcholinesterase (AChE) from the local fish Clarias batrachus is reported. AChE was assayed according to the modified method of Ellman. Screening of insecticide and heavy metals showed that carbofuran and carbaryl strongly inhibited C. batrachus AChE. The inhibition concentration (IC) IC50 values (and the 95% confidence interval) for both carbofuran and carbaryl inhibition on C. batrachus AChE at 6.66 (5.97-7.52) and 130.00 (119.3-142.5) microg l(-1), respectively was within the IC50 range of Electrophorus electricus at 6.20 (6.03-6.39) and 133.01 (122.40-145.50) microg l(-1), respectively and were much lower than bovine AChE at 20.94 (19.53-22.58) and 418.80 (390.60-451.60) microg l(-1), respectively. The results showed that C. batrachus have the potential to be used as a cheaper and more readily available source of AChE than other more commercially available sources.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  14. 2-Furoic piperazide derivatives as promising drug candidates of type 2 diabetes and Alzheimer's diseases: In vitro and in silico studies
    Abbasi MA, Hassan M, Ur-Rehman A, Siddiqui SZ, Hussain G, Shah SAA, et al.
    Comput Biol Chem, 2018 Dec;77:72-86.
    PMID: 30245349 DOI: 10.1016/j.compbiolchem.2018.09.007
    The heterocyclic compounds have been extensively reported for their bioactivity potential. The current research work reports the synthesis of some new multi-functional derivatives of 2-furoic piperazide (1; 1-(2-furoyl)piperazine). The synthesis was initiated by reacting the starting compound 1 with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) in a basic, polar and protic medium to obtain the parent sulfonamide 3 which was then treated with different electrophiles, 4a-g, in a polar and aprotic medium to acquire the designed molecules, 5a-g. These convergent derivatives were evaluated for their inhibitory potential against α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Acarbose was used as a reference standard for α-glucosidase inhibition while eserine for AChE and BChE inhibition. Some of the synthesized compounds were identified as promising inhibitors of these three enzymes and their bioactivity potentials were also supported by molecular docking study. The most active compounds among the synthetic analogues might be helpful in drug discovery and development for the treatment of type 2 diabetes and Alzhiemer's diseases.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  15. 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: Cholinesterase Inhibitors/chemistry*
  16. Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies
    Chigurupati S, Selvaraj M, Mani V, Selvarajan KK, Mohammad JI, Kaveti B, et al.
    Bioorg Chem, 2016 08;67:9-17.
    PMID: 27231830 DOI: 10.1016/j.bioorg.2016.05.002
    The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68±0.13μM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77±0.25μM and IC50: 12.59±0.21μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0.74±0.09μM) and with DPPH and ABTS radical scavenging activity (IC50: 13.52±0.62μM and IC50: 13.13±0.85μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  17. In vitro evaluation and in silico screening of synthetic acetylcholinesterase inhibitors bearing functionalized piperidine pharmacophores
    Brahmachari G, Choo C, Ambure P, Roy K
    Bioorg Med Chem, 2015 Aug 01;23(15):4567-4575.
    PMID: 26105711 DOI: 10.1016/j.bmc.2015.06.005
    A series of densely functionalized piperidine (FP) scaffolds was synthesized following a diastereoselective one-pot multicomponent protocol under eco-friendly conditions. The FPs were evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activity, and in silico studies for all the target compounds were carried out using pharmacophore mapping, molecular docking and quantitative structure-activity relationship (QSAR) analysis in order to understand the structural features required for interaction with the AChE enzyme and the key active site residues involved in the intermolecular interactions. Halogenation, nitration or 3,4-methylenedixoxy-substitution at the phenyl ring attached to the 2- and 6-positions of 1,2,5,6-tetrahydropyridine nucleus in compounds 14-17, 19, 20, 24 and 26 greatly enhanced the AChE inhibitory activity. The docking analysis demonstrated that the inhibitors are well-fitted in the active sites. The in silico studies enlighten the future course of studies in modifying the scaffolds for better therapeutic efficacy against the deadly Alzheimer's disease.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  18. An efficient ionic liquid mediated synthesis, cholinesterase inhibitory activity and molecular modeling study of novel piperidone embedded α,β-unsaturated ketones
    Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Khaw KY, et al.
    Med Chem, 2014;10(5):512-20.
    PMID: 24138113
    A series of hitherto unreported piperidone embedded α,β-unsaturated ketones were synthesized efficiently in ionic solvent and evaluated for cholinesterase inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Most of the synthesized compounds displayed good enzyme inhibition; therein compounds 7i and 7f displayed significant activity against AChE with IC50 values of 1.47 and 1.74 µM, respectively. Compound 6g showed the highest BChE inhibitory potency with IC50 value of 3.41 µM, being 5 times more potent than galanthamine. Molecular modeling simulation was performed using AChE and BChE receptors extracted from crystal structure of human AChE and human BChE to determine the amino acid residues involved in the binding interaction of synthesized compounds and their relevant receptors.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry*
  19. Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-β aggregation
    Simoni E, Bartolini M, Abu IF, Blockley A, Gotti C, Bottegoni G, et al.
    Future Med Chem, 2017 06;9(10):953-963.
    PMID: 28632446 DOI: 10.4155/fmc-2017-0039
    AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network.

    METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways.

    RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation.

    CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process.

    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
  20. A facile chemo-, regio- and stereoselective synthesis and cholinesterase inhibitory activity of spirooxindole-pyrrolizine-piperidine hybrids
    Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Perumal S, et al.
    Bioorg Med Chem Lett, 2013 May 15;23(10):2979-83.
    PMID: 23570788 DOI: 10.1016/j.bmcl.2013.03.027
    A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant cholinesterase inhibitory activity. Among the compounds screened, 8g and 8e, showed maximum inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE) with IC50 values of 3.33 and 3.13μM, respectively.
    Matched MeSH terms: Cholinesterase Inhibitors/chemistry
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