scholarly journals Volatile terpenoids as potential drug leads in Alzheimer’s disease

2017 ◽  
Vol 15 (1) ◽  
pp. 332-343 ◽  
Author(s):  
Karolina A. Wojtunik-Kulesza ◽  
Katarzyna Targowska-Duda ◽  
Katarzyna Klimek ◽  
Grażyna Ginalska ◽  
Krzysztof Jóźwiak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mtt Assay ◽  
Inhibitory Activity ◽  
Biological Activities ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Docking Simulations ◽  
Ache Inhibitory Activity ◽  
Volatile Terpenoids

AbstractAlzheimer’s disease (AD) is by far the most prevalent of all known forms of dementia. Despite wide-spread research, the main causes of emergence and development of AD have not been fully recognized. Natural, low-molecular, lipophilic terpenoids constitute an interesting group of secondary plant metabolites, that exert biological activities of possible use in the prevention and treatment of AD. In order to identify secondary metabolites possessing both antioxidant activity and the potential to increase the level of acetylcholine, selected terpenoids have been screened for possible acetylcholinesterase inhibitory activity by use of two methods, namely Marston (chromatographic assay) and Ellman (spectrophotometric assay). In order to describe the interaction between terpenes and AChE active gorge, molecular docking simulations were performed. Additionally, all analyzed terpenes were also evaluated for their cytotoxic properties against two normal cell lines using MTT assay. The obtained results show that: carvone (6), pulegone (8) and γ-terpinene (7) possess desirable AChE inhibitory activity. MTT assay revealed low or lack of cytotoxicity of these metabolites. Thus, among the investigated terpenes, carvone (6), pulegone (8) and y-terpinene (7) can be recognized as compounds with most promising activities in the development of multi-target directed ligands.

Development of Phthalimide-Donepezil Hybrids as Potent Multitarget- Directed Ligands for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 17 (9) ◽  
pp. 1155-1163
Author(s):  
Lintao Yu ◽  
Jian Shi ◽  
Xinfeng Cheng ◽  
Keren Wang ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Biological Activities ◽  
Docking Study ◽  
Binding Mode ◽  
Mao B ◽  
Ic50 Value ◽  
Ache Inhibitory Activity

Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD. Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/ MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode. Results: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross the blood-brain barrier in vitro. Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.

An integrated strategy for rapid screening of multi-target lead compounds for the treatment of Alzheimer's disease from traditional Chinese medicines by UHPLC combined with high-throughput screening: A case study on Salviae Miltiorrhizae Radix et Rhizoma

2021 ◽  
Vol 17 ◽  
Author(s):  
Minmin Zhang ◽  
Siduo Zhou ◽  
Wei Liu ◽  
Huijiao Yan ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Throughput ◽  
Inhibitory Activity ◽  
High Throughput Screening ◽  
Hplc Analysis ◽  
Salviae Miltiorrhizae ◽  
Salviae Miltiorrhizae Radix ◽  
Ache Inhibitory Activity

Background: Salviae Miltiorrhizae Radix et Rhizoma (Red Sage root) is widely used in traditional Chinese medicine (TCM) for the treatment of Alzheimer’s disease (AD) with demonstrated curative effects, based on the concept of "one drug with multiple therapeutic targets," which appears to be a good strategy for AD treatment. Objective: This study aimed to develop of high-throughput screening (HTS) method for multi-therapeutic target components found in complex TCMs, which are active against AD, using Red Sage root as the case study. Method: Acetylcholinesterase (AChE) inhibitors (AChEIs) from Red Sage root extracts were pre-screened by ultrafiltration-HPLC (UF-HPLC) analysis, in which AChE was added to the extract and then ultrafiltered to remove non-binding compounds. Potential AChEIs were identified by HPLC analysis of compounds bound to AChE. A microplate-based HTS was then used to quantify the AChE inhibitory activity and antioxidant activity of the pre-screened compounds. Results: Pre-screening found ten potential inhibitors, which were identified by ESI-TOF/MS; six of these were purified by semi-preparative HPLC: Oleoyl neocryptotanshinone (1), Dihydrotanshinone Ⅰ (2), Cryptotanshinone (3), Tanshinone Ⅰ (4), Tanshinone ⅡA (5) and Miltirone (6). All six compounds had good AChE inhibitory activity and weak DPPH scavenging capacity. Conclusion: This study provides a platform and technology support for the rapid discovery of multi-target components, potentially active against AD, from complex TCMs and with strong potential for adaptation to the discovery of treatments for other diseases.

scholarly journals Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer’s Disease Therapy

2017 ◽  
Vol 11 (1) ◽  
pp. 24-37 ◽  
Author(s):  
Gerard A. K. Teponnou ◽  
Jacques Joubert ◽  
Sarel F. Malan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Inhibitory Activity ◽  
Biological Activities ◽  
Radical Scavenging ◽  
Free Radical Scavenging ◽  
Linker Chain ◽  
Chain Lengths ◽  
Free Radical Scavenging Activities

The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer’s disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety (8a-8d) showed moderate to high TcAChE inhibition (IC50: 17.37 - 2200 nM), eqBuChE inhibition (IC50: 3.16 – 128.82 nM) and free radical scavenging activities (IC50: 11.48 – 49.23 µM). The hybrids with longer linker chain lengths in general showed better ChE inhibitory activity. As expected, free radical scavenging activities were not significantly affected by varying linker chain lengths. The hybrid compound containing the tryptoline moiety linked with a 7 carbon spacer to tacrine (14) displayed the best AChE and BuChE inhibitory activity (IC50 = 17.37 and 3.16 nM). Docking experiments exhibited that compounds 8d and 14 were able to bind to both the CAS and PAS of TcAChE and eqBuChE, suggesting that they will be able to inhibit ChE induced Aβ aggregation. Novel multi-target agents that exhibit good ChE inhibition (8d and 14) and anti-oxidant (8d) activity were identified as suitable candidates for further investigation.

scholarly journals A Platform for Screening Potential Anticholinesterase Fractions and Components Obtained fromAnemarrhena asphodeloidesBge for Treating Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yu Sun ◽  
Ying Peng ◽  
Lin-Guang Li ◽  
Li-Wei Zheng ◽  
Dong-Ju Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Memory Loss ◽  
Symptomatic Treatment ◽  
Ache Inhibitory Activity ◽  
Screening Platform ◽  
Ellman’S Method ◽  
Anemarrhena Asphodeloides ◽  
Ethanol Fraction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. Cholinesterase inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease to enhance central cholinergic transmission. In this study, a bioactivity-oriented screening platform based on a modified Ellman’s method and HPLC-QTOF MS technique was developed to rapidly screen active agents ofAnemarrhena asphodeloidesBge. The 60% ethanol fraction from an ethyl acetate extract exhibited the most potential anticholinesterase activity. Fifteen steroid saponins were identified by the mass spectrum, standards and literature reports. Twenty-five compounds were isolated from the active fraction. The results showed that compounds with the C6–C3–C6skeleton probably had both AChE and BuChE inhibitory activities. Xanthone and benzene derivatives exhibited no or little activity. Lignans showed weak BuChE inhibitory activity. The steroidal saponins demonstrated moderate or weak AChE inhibitory activity.

scholarly journals Evaluation of Acetylcholinesterase Inhibitory Activity of Fractions from Mahonia nepalensis (Berberidaceae) Extract

2017 ◽  
Vol 33 (2) ◽  
Author(s):  
Bui Thanh Tung ◽  
Phan Ke Son ◽  
Dang Kim Thu ◽  
Nguyen Thanh Hai ◽  
Nguyen Xuan Bach ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Colorimetric Method ◽  
Dependent Manner ◽  
Etoh Extract ◽  
Ache Inhibitors ◽  
Ache Inhibitory Activity ◽  
Etoac Fraction ◽  
Promising Source

Acetylcholinesterase (AChE) is a key target in the treatment of Alzheimer’s disease. Principal role of AChE hydrolyzes the neurotransmiter acetylcholine. Medicinal plants are the potential source of AChE inhibitors. In this study, we studied the AChE inhibitory activities of extraction  Mahonia nepalensis. This medicianl plant was extracted with ethanol 96% and subsequently fractionated with n-hexane, ethyl acetate (EtOA) and n-butanol (n-BuOH) solvents. These fractions were evaluated the AChE inhibitory activity by Ellman’s colorimetric method.  Results showed that n-BuOH fraction had the strongest AChE inhibitory activity, followed by EtOH extract and the EtOAc fraction was the weakest. The n-BuOH fraction inhibited AChE activity in a dose-dependent manner with an IC50 value of 3.38 ± 0.07 μg/mL. Detailed kinetic analysis indicated that n-BuOH fraction was mixed inhibiton type with Ki value of 3.416 ± 0.05 µg/mL. Our  data suggests that  the  Mahonia nepalensis may be  a  promising  source  of  AChE  inhibitors  for Alzheimer’s disease.

scholarly journals Acetylcholinesterase Inhibitor From Tabernaemontana pandacaqui Flowers

2020 ◽  
Vol 15 (3) ◽  
pp. 1934578X2091148
Author(s):  
Anan Athipornchai ◽  
Pattrapon Ketpoo ◽  
Rungnapha Saeeng
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ethyl Acetate ◽  
Inhibitory Activity ◽  
Acetylcholinesterase Inhibitor ◽  
Ethyl Acetate Fraction ◽  
Spectroscopic Techniques ◽  
Active Constituent ◽  
Ache Inhibitory Activity ◽  
Relationship Of

The inhibition of acetylcholinesterase (AChE) is still considered a strategy for the treatment of Alzheimer’s disease. The aim of this study was the search for potential drugs from natural sources which can inhibit AChE. The methanol extract of fresh flowers of Tabernaemontana pandacaqui was partitioned with n-hexane and ethyl acetate. All extracts were evaluated for AChE inhibitory activity. The ethyl acetate fraction, which showed the strongest AChE inhibitory activity, was fractionated using various chromatographic techniques, leading to the isolation of 6 compounds (1-6), which were identified mainly by spectroscopic techniques; this is the first report of these compounds from T. pandacaqui flowers. Astragalin (6) was the major active constituent. The structure-AChE inhibitory activity relationship of 6 and its derivatives was studied. The results suggest that T. pandacaqui flowers and its flavonoid compounds could be potentially used for the treatment of Alzheimer’s disease.

In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

2020 ◽  
Vol 20 ◽  
Author(s):  
Dnyaneshwar Baswar ◽  
Abha Sharma ◽  
Awanish Mishra
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
Biological Activities ◽  
Cholinergic Neurons ◽  
In Silico Screening ◽  
In Silico Studies ◽  
Bbb Permeability ◽  
Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

scholarly journals MOLECULAR DOCKING STUDIES ON THE THERAPEUTIC TARGETS OF ALZHEIMER'S DISEASE (AChE AND BChE) USING NATURAL BIOACTIVE ALKALOIDS

2016 ◽  
Vol 8 (12) ◽  
pp. 108
Author(s):  
Punabaka Jyothi ◽  
Kuna Yellamma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Neurodegenerative Disorder ◽  
Biological Activities ◽  
Neuropsychiatric Symptoms ◽  
Docking Studies ◽  
Kcal Mole ◽  
Molecular Docking Studies

Objective: Alzheimer’s disease (AD), a progressive neurodegenerative disorder with many cognitive and neuropsychiatric symptoms, is biochemically characterized by a significant decrease in the brain neurotransmitter Acetylcholine (ACh).Methods: In the present insilico study, six plant bioactive compounds namely Harmol, Vasicine, Harmaline, Harmine, Harmane and Harmalol (from P. Nigellastrum Bunge) were analyzed for their inhibitory role on AChE (Acetylcholinesterase) and BChE (Butyrylcholinesterase) activity by applying the molecular docking studies. Other parameters viz. determination of molecular interaction-based binding affinity values, protein-ligand interactions, Lipinski rule of five, functional properties and biological activities for the above compounds were also calculated by employing the appropriate bioinformatics tools.Results: The results of docking analysis clearly showed that Harmalol has highest binding affinity with AChE (-8.6 kcal/mole) and BChE (-8.0 kcal/mole) but it does not qualified the enzyme inhibitory activity, since it was exerted, and also has least percentage activity on AD and neurodegenerative disease. Whereas, the Harmine has been second qualified binding affinity (-8.4 kcal/mol) and first in other parameters when compared with Harmalol.Conclusion: Based on docking results and other parameters conducted, we are concluding that Harmine is the best compound for further studies to treat AD.Keywords: Alzheimer's disease (AD), Acetylcholinesterase, Butyrylcholinesterase, Lead Molecules

Sign in / Sign up

Export Citation Format

Share Document