Design, One-Pot Synthesis, and Evaluation of 7H-Thiazolo[3,2-b]-1,2,4-Triazin-7-One Derivatives as Dual Binding Site Acetylcholinesterase Inhibitors

2014 ◽  
Vol 884-885 ◽  
pp. 607-610
Author(s):  
Si Jie Liu ◽  
Lan Xiang Shi ◽  
Jing Yu He ◽  
Li Bo Cui
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Colorimetric Assay ◽  
Acetylcholinesterase Inhibitors ◽  
Positive Control ◽  
Huperzine A ◽  
One Pot ◽  
Control Drug ◽  
Ache Inhibitory Activity ◽  
Methyl Pyrrolidone

In order to study the the structure-AChE inhibitory activity relationships of 7H-thiazolo [3,2-b]-1,2,4-triazin-7-one derivatives, the 7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were designed by molecular docking, and readily prepared via a one-pot reaction in N-methyl pyrrolidone hydrosulfate ([Hnmp]HSO4) lonic liquid. The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control drug. Most of the target compounds exhibited more than 50% inhibition at 10μM.

scholarly journals In vivo hypotensive effect and in vitro inhibitory activity of some Cyperaceae species

2013 ◽  
Vol 49 (4) ◽  
pp. 803-809
Author(s):  
Monica Lacerda Lopes Martins ◽  
Henrique Poltronieri Pacheco ◽  
Iara Giuberti Perini ◽  
Dominik Lenz ◽  
Tadeu Uggere de Andrade ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Colorimetric Assay ◽  
Hypotensive Effect ◽  
Ace Inhibition ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Total Phenolic ◽  
Before And After

In 1820, French naturalist August Saint Hillaire, during a visit in Espírito Santo (ES), a state in southeastern Brazil, reported a popular use of Cyperaceae species as antidote to snake bites. The plant may even have a hypotensive effect, though it was never properly researched. The in vitro inhibitory of the angiotensin converting enzyme (ACE) activity of eigth ethanolic extracts of Cyperaceae was evaluated by colorimetric assay. Total phenolic and flavonoids were determined using colorimetric assay. The hypotensive effect of the active specie (Rhychonospora exaltata, ERE) and the in vivo ACE assay was measured in vivo using male Wistar Kyoto (ERE, 0.01-100mg/kg), with acetylcholine (ACh) as positive control (5 µg/kg, i.v.). The evaluation of ACE in vivo inhibitory effect was performed comparing the mean arterial pressure before and after ERE (10 mg/kg) in animals which received injection of angiotensin I (ANG I; 0,03, 03 and 300 µg/kg, i.v.). Captopril (30 mg/kg) was used as positive control. Bulbostylis capillaris (86.89 ± 15.20%) and ERE (74.89 ± 11.95%, ERE) were considered active in the in vitro ACE inhibition assay, at 100 µg/mL concentration. ACh lead to a hypotensive effect before and after ERE's curve (-40±5% and -41±3%). ERE showed a dose-dependent hypotensive effect and a in vivo ACE inhibitory effect. Cyperaceae species showed an inhibitory activity of ACE, in vitro, as well as high content of total phenolic and flavonoids. ERE exhibited an inhibitory effect on both in vitro and in vivo ACE. The selection of species used in popular medicine as antidotes, along with the in vitro assay of ACE inhibition, might be a biomonitoring method for the screening of new medicinal plants with hypotensive properties.

Delineating the pharmacophoric elements of huperzine A: importance of the unsaturated three-carbon bridge to its AChE inhibitory activity

1991 ◽  
Vol 34 (12) ◽  
pp. 3399-3402 ◽  
Author(s):  
Alan P. Kozikowski ◽  
Chris P. Miller ◽  
Fumio Yamada ◽  
Yuan Ping Pang ◽  
Jacqueline H. Miller ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Huperzine A ◽  
Ache Inhibitory Activity

An expedient microwave assisted regio- and stereoselective synthesis of spiroquinoxaline pyrrolizine derivatives and their AChE inhibitory activity

2017 ◽  
Vol 41 (2) ◽  
pp. 873-878 ◽  
Author(s):  
Adinarayana Murthy Akondi ◽  
Sowmya Mekala ◽  
Mannepalli Lakshmi Kantam ◽  
Rajiv Trivedi ◽  
L. Raju Chowhan ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Stereoselective Synthesis ◽  
Facile Synthesis ◽  
One Pot ◽  
Microwave Assisted ◽  
Ache Inhibitory Activity ◽  
The One

We report here an efficient protocol for the one-pot facile synthesis of spiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]heterocyclic scaffolds and their AChE inhibitory studies.

scholarly journals Regiospecific synthesis of 2,3-disubstituted indoles from isatins

2016 ◽  
Author(s):  
Artur Ulikowski ◽  
Anna Jaromin ◽  
Giorgia Brancolini ◽  
Luca Bellucci ◽  
Bartłomiej Furman
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Functional Group ◽  
Enzyme Inhibitors ◽  
Biologically Active ◽  
Special Importance ◽  
Indole Derivatives ◽  
Structural Element ◽  
Wide Range ◽  
Ache Inhibitory Activity

Indoles represent a structural element in a myriad of natural products and biologically active molecules. Of special importance are 2,3-disubstituted indoles. Thus, a number of methods for their synthesis have been described. However, these are often hampered by a number of limitations: they often offer poor regioselectivity and suboptimal functional group tolerance. Also, they can normally be adapted to the procurement of a small subclass of indoles only. We have developed an approach to 2,3-disubstituted indoles overcoming these obstacles. By selectively activating the amide carbonyl in isatin-derived oxindoles, we obtained a number of the title compounds in a regiospecific and functional group-tolerant manner. The methodology is normally characterized by excellent yields. The reaction proceeds by chemoselective partial reduction of the amide moiety to an iminium salt and a subsequent nucleophilic addition followed by dehydration, which furnishes the target indole. A number of nucleophiles, including C- and S-nucleophiles, have been examined. The obtained compounds were studied towards acetylcholinesterase (AChE) inhibitory activity, as the indole skeleton is often seen in the struc-ture of enzyme inhibitors. Cholinesterase inhibitors are used in the treatment of Alzheimer's disease, increasing available acetylcholine by decreasing the AChE activity. For the tested agents, properties like logP, logBBB (Blood-Brain Barier penetration) and Caco2 permeabilities were also calculated. Based on the predicted values, only two of them are able to penetrate into the CNS (central nervous system). Molecular docking was performed on the whole set of the syntesized indole derivatives, resulting in a wide range of AChE inhibitory activity. Molecular docking binding interactions reported the lowest energy conformations of the syntesized compounds and the key amino acid residues at the active binding site of AChE. The current synergy between computations and experiments provided the identification of the indole derivatives exhibiting the highest inhibitory activity. The presented results will provide theoretical guidance for further modification and optimization of the indole derivatives.

scholarly journals Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5319
Author(s):  
Rakesh Kumar Sharma ◽  
Manisha Singh ◽  
Khagendra Ghimeray ◽  
Pinky Juneja ◽  
Gagan Dev ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Neuroblastoma Cell ◽  
Acetylcholinesterase Inhibitors ◽  
Adenosine Monophosphate ◽  
Neuroblastoma Cell Line ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Mitochondrial Oxidative Stress ◽  
Nitric Oxide Release ◽  
Ache Inhibitory Activity

Imidazo[1,2-b]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-b]pyridazine compounds (5c and 5h) showed potent acetylcholinesterase (AChE) inhibitory activity (IC50 40–50 nM), which we have previously reported. In this study, we wanted to test the biological efficacy of these compounds. Cytotoxicity assays showed that compound 5h mediated greater cell death with over 43% of cells dead at 100 μM and activation of caspase 3-mediated apoptosis. On the other hand, compound 5c mediated a dose-dependent decrease in cell proliferation. Both compounds showed cell cycle arrest in the G0/G1 phase and reduced cellular ATP levels leading to activation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitochondrial oxidative stress. It has to be noted that all these effects were observed at doses beyond 10 μM, 200-fold above the IC50 for AChE inhibition. Both compounds also inhibited bacterial lipopolysaccharide-mediated cyclooxygenase-2 and nitric oxide release in primary rat microglial cells. These results suggested that the substituted imidazo (1,2-b) pyridazine compounds, which have potent AChE inhibitory activity, were also capable of antiproliferative, anti-migratory, and anti-inflammatory effects at higher doses.

scholarly journals Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds of Dimorphandra gardneriana and Platymiscium floribundum, native plants from Caatinga biome

2012 ◽  
Vol 32 (11) ◽  
pp. 1164-1168 ◽  
Author(s):  
Nadja S. Vila-Nova ◽  
Selene M. Morais ◽  
Maria J.C. Falcão ◽  
Claudia M.L. Bevilaqua ◽  
Fernanda C.M. Rondon ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
New Technologies ◽  
Colorimetric Assay ◽  
Positive Control ◽  
World Health ◽  
Control Drug ◽  
Caatinga Biome ◽  
Health Organization ◽  
Acetylcholinesterase Enzyme

In recent years, the Brazilian Health Ministry and the World Health Organization have supported research into new technologies that may contribute to the surveillance, new treatments, and control of visceral leishmaniasis within the country. In light of this, the aim of this study was to isolate compounds from plants of the Caatinga biome, and to investigate their toxicity against promastigote and amastigote forms of Leishmania infantum chagasi, the main responsible parasite for South American visceral leishmaniasis, and evaluate their ability to inhibit acetylcholinesterase enzyme (AChE). A screen assay using luciferase-expressing promastigote form and an in situ ELISA assay were used to measure the viability of promastigote and amastigote forms, respectively, after exposure to these substances. The MTT colorimetric assay was performed to determine the toxicity of these compounds in murine monocytic RAW 264.7 cell line. All compounds were tested in vitro for their anti-cholinesterase properties. A coumarin, scoparone, was isolated from Platymiscium floribundum stems, and the flavonoids rutin and quercetin were isolated from Dimorphandra gardneriana beans. These compounds were purified using silica gel column chromatography, eluted with organic solvents in mixtures of increasing polarity, and identified by spectral analysis. In the leishmanicidal assays, the compounds showed dose-dependent efficacy against the extracellular promastigote forms, with an EC50 for scoporone of 21.4µg/mL, quercetin and rutin 26 and 30.3µg/mL, respectively. The flavonoids presented comparable results to the positive control drug, amphotericin B, against the amastigote forms with EC50 for quercetin and rutin of 10.6 and 43.3µg/mL, respectively. All compounds inhibited AChE with inhibition zones varying from 0.8 to 0.6, indicating a possible mechanism of action for leishmacicidal activity.

scholarly journals Synergistic Inhibition of Acetylcholinesterase by Alkaloids Derived from Stephaniae Tetrandrae Radix, Coptidis Rhizoma and Phellodendri Chinensis Cortex

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4567 ◽  
Author(s):  
Xiang-Peng Kong ◽  
Etta Y.L. Liu ◽  
Zhi-Cong Chen ◽  
Miranda Li Xu ◽  
Anna X.D. Yu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Simulation ◽  
Huperzine A ◽  
Ache Inhibition ◽  
Active Components ◽  
Molecular Docking Simulation ◽  
Synergistic Inhibition ◽  
Ache Inhibitory Activity ◽  
Coptidis Rhizoma ◽  
Main Components

Alkaloids having acetylcholinesterase (AChE) inhibitory activity are commonly found in traditional Chinese medicine (TCM); for example, berberine from Coptis chinensis, galantamine from Lycoris radiata, and huperzine A from Huperzia serrata. In practice of TCM, Stephaniae Tetrandrae Radix (STR) is often combined with Coptidis Rhizoma (CR) or Phellodendri Chinensis Cortex (PCC) as paired herbs during clinical application. Fangchinoline from STR and coptisine and/or berberine from CR and/or PCC are active alkaloids in inhibiting AChE. The traditional usage of paired herbs suggests the synergistic effect of fangchinoline–coptisine or fangchinoline–berberine pairing in AChE inhibition. HPLC was applied to identify the main components in herbal extracts of STR, CR, and PCC, and the AChE inhibition of their main components was determined by Ellman assay. The synergism of herb combination and active component combination was calculated by median-effect principle. Molecular docking was applied to investigate the underlying binding mechanisms of the active components with the AChE protein. It was found that fangchinoline showed AChE inhibitory potency; furthermore, fangchinoline–coptisine/berberine pairs (at ratios of 1:5, 1:2, 1:1, and 2:1) synergistically inhibited AChE; the combination index (CI) at different ratios was less than one when Fa = 0.5, suggesting synergistic inhibition of AChE. Furthermore, the molecular docking simulation supported this enzymatic inhibition. Therefore, fangchinoline–coptisine/berberine pairs, or their parental herbal mixtures, may potentially be developed as a possible therapeutic strategy for Alzheimer’s patients.

scholarly journals The Cholinesterase Inhibitory Properties of Stephaniae Tetrandrae Radix

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5914
Author(s):  
Xiang-Peng Kong ◽  
Hai-Qin Ren ◽  
Etta Y. L. Liu ◽  
Ka-Wing Leung ◽  
Shu-Chen Guo ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Therapeutic Strategy ◽  
Catalytic Site ◽  
Huperzine A ◽  
Chinese Herbs ◽  
Anionic Site ◽  
Water Metabolism ◽  
Cholinesterase Inhibitory Activity ◽  
Ache Inhibitory Activity ◽  
Main Components

Stephaniae tetrandrae radix (STR) is a commonly used traditional Chinese medicine in alleviating edema by inducing diuresis. In the clinic, STR extracts or its components are widely used in the treatment of edema, dysuria, and rheumatism for the regulation of water metabolism. Furthermore, STR has been used in treating emotional problems for years by combining with other Chinese herbs. However, the material basis and mechanism of STR on the nervous system have not been revealed. Here, the main components of STR extracts with different extracting solvents were identified, including three major alkaloids, i.e., cyclanoline, fangchinoline, and tetrandrine. The cholinesterase inhibitory activity of STR extracts and its alkaloids was determined using the Ellman assay. Both cyclanoline and fangchinoline showed acetylcholinesterase (AChE) inhibitory activity, demonstrating noncompetitive enzyme inhibition. In contrast, tetrandrine did not show enzymatic inhibition. The synergism of STR alkaloids with huperzine A or donepezil was calculated by the median-effect principle. The drug combination of fangchinoline–huperzine A or donepezil synergistically inhibited AChE, having a combination index (CI) < 1 at Fa = 0.5. Furthermore, the molecular docking results showed that fangchinoline bound with AChE residues in the peripheral anionic site, and cyclanoline bound with AChE residues in the peripheral anionic site, anionic site, and catalytic site. In parallel, cyclanoline bound with butyrylcholinesterase (BChE) residues in the anionic site, catalytic site, and aromatic site. The results support that fangchinoline and cyclanoline, alkaloids derived from STR, could account for the anti-AChE function of STR. Thus, STR extract or its alkaloids may potentially be developed as a therapeutic strategy for Alzheimer’s patients.

scholarly journals Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1963 ◽  
Author(s):  
Sarra Boudriga ◽  
Saoussen Haddad ◽  
Vikneswaran Murugaiyah ◽  
Moheddine Askri ◽  
Michael Knorr ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Cycloaddition Reaction ◽  
Docking Study ◽  
X Ray Diffraction ◽  
Molecular Docking Study ◽  
Reaction Conditions ◽  
One Pot ◽  
X Ray ◽  
Cholinesterase Inhibitory Activity ◽  
Ache Inhibitory Activity

A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.

scholarly journals Regiospecific synthesis of 2,3-disubstituted indoles from isatins

2016 ◽  
Author(s):  
Artur Ulikowski ◽  
Anna Jaromin ◽  
Giorgia Brancolini ◽  
Luca Bellucci ◽  
Bartłomiej Furman
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Functional Group ◽  
Enzyme Inhibitors ◽  
Biologically Active ◽  
Special Importance ◽  
Indole Derivatives ◽  
Structural Element ◽  
Wide Range ◽  
Ache Inhibitory Activity

Indoles represent a structural element in a myriad of natural products and biologically active molecules. Of special importance are 2,3-disubstituted indoles. Thus, a number of methods for their synthesis have been described. However, these are often hampered by a number of limitations: they often offer poor regioselectivity and suboptimal functional group tolerance. Also, they can normally be adapted to the procurement of a small subclass of indoles only. We have developed an approach to 2,3-disubstituted indoles overcoming these obstacles. By selectively activating the amide carbonyl in isatin-derived oxindoles, we obtained a number of the title compounds in a regiospecific and functional group-tolerant manner. The methodology is normally characterized by excellent yields. The reaction proceeds by chemoselective partial reduction of the amide moiety to an iminium salt and a subsequent nucleophilic addition followed by dehydration, which furnishes the target indole. A number of nucleophiles, including C- and S-nucleophiles, have been examined. The obtained compounds were studied towards acetylcholinesterase (AChE) inhibitory activity, as the indole skeleton is often seen in the struc-ture of enzyme inhibitors. Cholinesterase inhibitors are used in the treatment of Alzheimer's disease, increasing available acetylcholine by decreasing the AChE activity. For the tested agents, properties like logP, logBBB (Blood-Brain Barier penetration) and Caco2 permeabilities were also calculated. Based on the predicted values, only two of them are able to penetrate into the CNS (central nervous system). Molecular docking was performed on the whole set of the syntesized indole derivatives, resulting in a wide range of AChE inhibitory activity. Molecular docking binding interactions reported the lowest energy conformations of the syntesized compounds and the key amino acid residues at the active binding site of AChE. The current synergy between computations and experiments provided the identification of the indole derivatives exhibiting the highest inhibitory activity. The presented results will provide theoretical guidance for further modification and optimization of the indole derivatives.

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