Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities

Alzheimer’s disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be and are being employed in this journey. In this review, four of the most promising strategies, alongside with its most promising agents under investigation or development are highlighted. Marine natural products (MNP) are a source of unique chemical structures with useful biological activities for AD treatment. One of the most promising compounds, a marine-derived acidic oligosaccharide (GV-971) just passed phase III clinical trials with a unique mechanism of action. Combination therapy and multitargeted-directed ligand therapy (MTDL) are also two important strategies, with several examples in clinical trials, based on the belief that the best approach for AD is a therapy capable of modulating multiple target pathways. Drug repurposing, a strategy that requires a smaller investment and is less time consuming, is emerging as a strong contender with a variety of pharmacological agents resurfacing in an attempt to identify a therapeutic candidate capable of modifying the course of this disease.

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Therapeutic Properties of Several Chemical Compounds from Salvia officinalis L. in Alzheimer’s Disease

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521999201230200209 ◽

2020 ◽

Vol 21 ◽

Author(s):

Georgiana Uță ◽

Denisa Ștefania Manolescu ◽

Speranța Avram

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Side Effects ◽

Chemical Compounds ◽

Natural Compounds ◽

Salvia Officinalis ◽

Chemical Structures ◽

In Silico Studies ◽

Wide Range ◽

Salvia Officinalis L

Background.: Currently, the pharmacological management in Alzheimer's disease is based on several chemical structures, represented by acetylcholinesterase and N-methyl-D-aspartate (NMDA) receptor ligands, with still unclear molecular mechanisms, but severe side effects. For this reason, a challenge for Alzheimer's disease treatment remains to identify new drugs with reduced side effects. Recently, the natural compounds, in particular certain chemical compounds identified in the essential oil of peppermint, sage, grapes, sea buckthorn, have increased interest as possible therapeutics. Objectives.: In this paper, we have summarized data from the recent literature, on several chemical compounds extracted from Salvia officinalis L., with therapeutic potential in Alzheimer's disease. Methods.: In addition to the wide range of experimental methods performed in vivo and in vitro, also we presented some in silico studies of medicinal compounds. Results. Through this mini-review, we present the latest information regarding the therapeutic characteristics of natural compounds isolated from Salvia officinalis L. in Alzheimer's disease. Conclusion.: Thus, based on the information presented, we can say that phytotherapy is a reliable therapeutic method in a neurodegenerative disease.

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

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201119144535 ◽

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.

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Volatile terpenoids as potential drug leads in Alzheimer’s disease

Open Chemistry ◽

10.1515/chem-2017-0040 ◽

2017 ◽

Vol 15 (1) ◽

pp. 332-343 ◽

Cited By ~ 7

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.

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

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i12.14833 ◽

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

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THE BIOLOGICAL ACTIVITIES AND FUNCTION OF THE AMYLOID PRECURSOR PROTEIN OF ALZHEIMER’S DISEASE

MOLECULAR BIOLOGY OF ALZHEIMER’S DISEASE ◽

10.4324/9780203303610_chapter_4 ◽

2010 ◽

Author(s):

GERD MULTHAUP ◽

COLIN L MASTERS ◽

KONRAD BEYREUTHER ◽

ROBERTO CAPPAI

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Biological Activities ◽

Precursor Protein ◽

And Function

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Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer’s disease

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2020.112163 ◽

2020 ◽

Vol 192 ◽

pp. 112163 ◽

Cited By ~ 8

Author(s):

Han Li ◽

Yuzhi Liu ◽

Danni Tian ◽

Lei Tian ◽

Xingke Ju ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Biological Activities

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Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

BMC Chemistry ◽

10.1186/s13065-020-00715-0 ◽

2020 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Hajar Karimi Askarani ◽

Aida Iraji ◽

Arezoo Rastegari ◽

Syed Nasir Abbas Bukhari ◽

Omidreza Firuzi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Biological Activities ◽

Neuroprotective Effects ◽

Design And Synthesis ◽

Catalytic Active Site ◽

Aβ Aggregation ◽

Multifunctional Agents ◽

Potential Use

Abstract To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

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Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer’s Disease and Brain Ischemia

Cells ◽

10.3390/cells9112351 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2351 ◽

Cited By ~ 1

Author(s):

Veronika Prikhodko ◽

Daria Chernyuk ◽

Yurii Sysoev ◽

Nikita Zernov ◽

Sergey Okovityi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Ischemia ◽

Brain Ischemia ◽

In Vivo Studies ◽

Potential Drug ◽

Drug Candidates ◽

Chemical Structures ◽

Trpc6 Channel

Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca2+. Its Ca2+-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models. Thus, in order to protect neurons from Alzheimer’s disease and cerebral ischemia, proper TRPC6 channels modulators have to be used. TRPC6 channels modulators are an emerging research field. New chemical structures modulating the activity of TRPC6 channels are being currently discovered. The recent publication of the cryo-EM structure of TRPC6 channels should speed up the discovery process even more. This review summarizes the currently available information about potential drug candidates that may be used as basic structures to develop selective, highly potent TRPC6 channel modulators to treat neurodegenerative disorders, such as Alzheimer’s disease and cerebral ischemia.

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The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review

Chinese Medicine ◽

10.1186/s13020-021-00486-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Wenwen Zhang ◽

Fangling Zhang ◽

Qichao Hu ◽

Xiaolin Xiao ◽

Linbo Ou ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Ischaemia ◽

Neuronal Damage ◽

Biological Activities ◽

Protective Effects ◽

Specific Circumstance ◽

Gardenia Jasminoides ◽

Cerebral Diseases

AbstractWith the advanced discoveries in the field of pathogenesis, a series of cerebral diseases, such as cerebral ischaemia, Alzheimer's disease, and depression, have been found to have multiple signalling targets in the microenvironment. Only a few existing agents have been shown to have curative effects due to this specific circumstance. In recent decades, active ingredients isolated from natural plants have been shown to be crucial for original drug development. Geniposide, mainly extracted from Gardenia jasminoides Ellis, is representative of these natural products. Geniposide demonstrates various biological activities in the treatment of cerebral, cardiovascular, hepatic, tumorous, and other diseases. The multiple protective effects of geniposide on the brain have especially drawn increasing attention. Thus, this article specifically reviews the characteristics of current models of cerebral ischaemia and illustrates the possible effects of geniposide and its pathogenetic mechanisms on these models. Geniposide has been shown to significantly reduce the area of cerebral infarction and alleviate neuronal damage and necrosis mainly by inhibiting inflammatory signals, including NLRP3, TNF-α, IL-6, and IL-1β. Neuronal protection was also involved in activating the PI3K/Akt and Wnt/catenin pathways. Geniposide was able to increase autophagy and inhibit apoptosis by regulating the function of mTOR in treating Alzheimer's disease. Geniposide has also been shown to act as a glucagon-like peptide-1 receptor (GLP-1R) agonist to reduce amyloid plaques and inhibit oxidative stress to alleviate memory impairment as well as synaptic loss. Moreover, geniposide has been shown to exert antidepressant effects primarily by regulating the hypothalamic–pituitary–adrenal (HPA) axis. Detailed explorations have shown that the biological activities of inhibiting inflammatory cytokine secretion, alleviating oxidative stress, and suppressing mitochondrial damage are also involved in the mechanism of action of geniposide. Therefore, geniposide is a promising agent awaiting further exploration for the treatment of cerebral diseases via various phenotypes or signalling pathways.

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