Synthesis and Cholinesterase Inhibitory Activity of N-Phosphorylated/ N-Tiophosphorylated Tacrine

Background: Alzheimer’s disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease. Objective: Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer’s disease (AD) agents. Methods: 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS. Results: The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition. Conclusion: All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).

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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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Synthesis and DPPH scavenging assay of reserpine analogues, computational studies and in silico docking studies in AChE and BChE responsible for Alzheimer's disease

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502015000100006 ◽

2015 ◽

Vol 51 (1) ◽

pp. 53-61 ◽

Cited By ~ 2

Author(s):

Muhammad Yar ◽

Muhammad Arshad ◽

Ariba Farooq ◽

Mazhar Amjad Gilani ◽

Khurshid Ayub ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Free Radicals ◽

In Silico ◽

Density Functional ◽

Neurodegenerative Disorder ◽

Antioxidant Properties ◽

Docking Studies ◽

In Silico Docking ◽

Ic50 Values

Alzheimer's disease (AD) is a fast growing neurodegenerative disorder of the central nervous system and anti-oxidants can be used to help suppress the oxidative stress caused by the free radicals that are responsible for AD. A series of selected synthetic indole derivatives were biologically evaluated to identify potent new antioxidants. Most of the evaluated compounds showed significant to modest antioxidant properties (IC50 value 399.07 140.0±50 µM). Density Functional Theory (DFT) studies were carried out on the compounds and their corresponding free radicals. Differences in the energy of the parent compounds and their corresponding free radicals provided a good justification for the trend found in their IC50 values. In silico, docking of compounds into the proteins acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are well known for contributing in AD disease, was also performed to predict anti-AD potential.

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Naturally Inspired Pyrimidines Analogues for Alzheimer’s Disease

Current Neuropharmacology ◽

10.2174/1570159x18666201111110136 ◽

2020 ◽

Vol 19 (2) ◽

pp. 136-151

Author(s):

Shivani Singh ◽

Meenakshi Dhanawat ◽

Sumeet Gupta ◽

Deepak Kumar ◽

Saloni Kakkar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multicomponent Reactions ◽

Neurodegenerative Disorder ◽

The Body ◽

New Drugs ◽

Atom Economy ◽

Step Process ◽

One Step ◽

Made In

: Alzheimer’s disease (AD) is a multifarious and developing neurodegenerative disorder. The treatment of AD is still a challenge and availability of drug therapy on the basis of symptoms is not up to the mark. In the context of existence, which is getting worse for the human brain, it is necessary to take care of all critical measures. The disease is caused due to multidirectional pathology of the body, which demands the multi-target-directed ligand (MTDL) approach. This gives hope for new drugs for AD, summarized here in with the pyrimidine based natural product inspired molecule as a lead. The review is sufficient in providing a list of chemical ingredients of the plant to cure AD and screen them against various potential targets of AD. The synthesis of a highly functionalized scaffold in one step in a single pot without isolating the intermediate is a challenging task. In few examples, we have highlighted the importance of this kind of reaction, generally known as multi-component reaction. Multi-component is a widely accepted technique by the drug discovery people due to its high atom economy. It reduces multi-step process to a one-step process, therefore the compounds library can be made in minimum time and cost. This review has highlighted the importance of multicomponent reactions by giving the example of active scaffolds of pyrimidine/fused pyrimidines. This would bring importance to the fast as well as smart synthesis of bio-relevant molecules.

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Drug Repurposing for Alzheimer’s Disease based on Protein-Protein Interaction Network

10.21203/rs.3.rs-398606/v1 ◽

2021 ◽

Author(s):

Negar Sadat Soleimani Zakeri ◽

Saeid Pashazadeh ◽

Habib MotieGhader

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Interactions ◽

Neurodegenerative Disorder ◽

Gentian Violet ◽

Interaction Network ◽

New Drugs ◽

Bipartite Network ◽

Medical Studies ◽

Gene Complexes

Abstract Background: Alzheimer's disease (AD) is known as a critical neurodegenerative disorder. It worsens as symptoms concerning dementia grow severe over the years. Due to the globalization of Alzheimer’s disease, its prevention and treatment is vital. This study proposes a method to extract substantial gene complexes and accomplish an enrichment analysis to introduce the most significant biological procedures. The next step is extracting the drugs related to AD and introduce some new drugs which may be useful for this disease. Results: To this end, protein-protein interactions (PPI) network was utilized to extract five meaningful gene complexes functionally interconnected. The next step was to construct a five bipartite network representing the genes of each group and their target miRNAs. Finally, a complete network including all the genes related to each gene complex group and genes’ target drug was illustrated. medical studies and publications were analyzed thoroughly to introduce AD-related drugs. Conclusions: This analysis proves the accuracy of the proposed method in this study. Then, new drugs were introduced that can be experimentally examined as future work. RALOXIFENE, GENTIAN VIOLET are two new drugs, which have not been introduced as AD-related drugs in previous scientific and medical studies, recommended by the method of this study. These two drugs.

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The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

Journal of Endocrinology ◽

10.1530/joe-18-0532 ◽

2019 ◽

Vol 240 (2) ◽

pp. R47-R72 ◽

Cited By ~ 6

Author(s):

Lenka Maletínská ◽

Andrea Popelová ◽

Blanka Železná ◽

Michal Bencze ◽

Jaroslav Kuneš

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Energy Homeostasis ◽

Neurodegenerative Disorder ◽

Experimental Studies ◽

The Elderly ◽

Experimental Models ◽

New Drugs ◽

Neuroprotective Effects ◽

The Impact

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

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Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

Molecules ◽

10.3390/molecules26185582 ◽

2021 ◽

Vol 26 (18) ◽

pp. 5582

Author(s):

Alfred Ngenge Tamfu ◽

Selcuk Kucukaydin ◽

Balakyz Yeskaliyeva ◽

Mehmet Ozturk ◽

Rodica Mihaela Dinica

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholinesterase Inhibitors ◽

High Efficiency ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

New Drugs ◽

Cholinesterase Inhibition ◽

Natural Sources ◽

Long Term Treatment

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease.

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Utility of animal models of Alzheimer’s disease in food bioactive research

Journal of Food Bioactives ◽

10.31665/jfb.2020.13255 ◽

2021 ◽

Vol 13 ◽

Author(s):

Klaus W. Lange

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Clinical Success ◽

Treatment Strategies ◽

New Drugs ◽

Preclinical Research ◽

Novel Treatment Strategies

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by globally impaired cognition. AD research in animals has shown a substantial deficit in translational relevance. The most extensively used transgenic mouse models overexpress human genes associated with rare familial early-onset AD, which results in the formation of amyloid plaques. However, the most common form of AD (late-onset sporadic AD) is a multifactorial disorder involving different cytotoxic factors, including neurofibrillary pathology. Transgenic mice studies have been valuable in elucidating pathogenetic mechanisms that may be relevant to human AD. However, their utility in the development of novel treatment strategies and as preclinical testbeds of new drugs has been unsatisfactory. Animal models have so far failed to demonstrate predictive value in regard to novel therapies of AD, including the use of bioactive food components. While many therapeutic approaches assessed in animals have shown promising results, attempts to translate these findings to people with AD have been disappointing. Food scientists should be aware that the available animal models appear to be unable to predict clinical success in humans. Therefore, food bioactive research should focus on human-centric preventive approaches to AD in clinically meaningful settings rather than on highly questionable preclinical research in animals.

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Design, Synthesis and Biological Evaluation of New Cycloalkyl Fused Quinolines Tethered to Isatin Schiff Bases as Cholinesterase Inhibitors

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666201211092138 ◽

2020 ◽

Vol 23 ◽

Author(s):

Baswaraju Macha ◽

Ravindra Kulkarni ◽

Anil Kumar Garige ◽

Rambabu Palabindala ◽

Raghuramrao Akkinepally ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Schiff Bases ◽

Active Site ◽

Inhibitory Activity ◽

Docking Studies ◽

Behavioral Studies ◽

Cholinesterase Inhibitory Activity ◽

Butyryl Cholinesterase

Aims and Objective: Alzheimer’s disease is now a most prevalent neuro degenerative disease of central nervous system leading to dementia in elderly aged population. Numerous pathological changes have been associated in the progression of Alzheimer’s disease. One of such pathological hypothesis is declined cholinergic activity which eventually affects cognitive and memory deficits. Inhibition cholinesterases will apparently elevate acetyl choline levels which is benefactor on cognitive symptoms of the disease. This manuscript describes the new tacrine derivatives tethered to isatin Schiff bases through alkanoyl linker and screened for cholinesterase inhibitory activity. Materials and Methods: Tacrine and two more cycloalkyl ring fused quinolones were synthesized and converted to Ncycloalkyl fused quinoline chloroamides. Isatin Schiff bases were also synthesized by the reaction between isatin and substituted aromatic anilines and in subsequent reaction, isatin Schiff bases were reacted with cycloalkyl fused quinolones to afford anticipated compounds 10a-i, 11a-i and 12a-i. All the compounds have been screened for acetyl and butyryl cholinesterase inhibitory activity and in vivo behavioral studies. Binding interactions of the desired compounds have also been studied by docking them in active site of both cholinesterases. Results: Three compounds 12d, 12e and 12h with propionyl and butyroyl linker between amine and isatin Schiff base scaffold have shown potent acetyl and butyryl cholinesterase inhibitory activity. However most potent cholinesterase inhibitor was 13d with IC50 value of 0.71±0.004 and 1.08±0.02 μM against acetyl and butyryl cholinesterases respectively. The hepatotoxicity of potent compounds revealed that the tested compounds were less hepatotoxic than tacrine and also exhibited encouraging in vivo behavioral studies in test animals. Docking studies of all the molecules disclosed close hydrogen bond interactions within the binding site of both cholinesterases. Conclusion: New cycloalkyl fused quinolones tethered with alkoyl linker to isatin Schiff bases endowed significant and potent cholinesterase inhibitory activities. Few of the compounds have also exhibited lesser hepatotoxicity and all the synthesized compounds were good in behavioral studies. Molecular docking studies also indicated close interactions in active site of cholinesterases.

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A Systematic Review on the Role of Natural Products in Modulating the Pathways in Alzheimer’s Disease

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000405 ◽

2017 ◽

Vol 87 (1-2) ◽

pp. 99-116 ◽

Cited By ~ 5

Author(s):

Sandip T. Auti ◽

Yogesh A. Kulkarni

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Conventional Medicine ◽

Neuronal Cell ◽

Specific Effect ◽

New Drugs ◽

Disease Pathways

Abstract. Alzheimer’s disease (AD) is the most common neurodegenerative disorder to date, with no cure or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles in brain. Despite extensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look for alternative therapies and new drugs. Use of natural products in medicine has gained popularity in recent years and several natural compounds with neuroprotective effects have been studied in detail. Some of them target the disease pathways and improve cognition by directly affecting amyloidogenesis, programmed cell death and increase neuronal cell survival. Currently, phytochemicals like polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received a special attention from the scientific community against the pathological processes in conditions like cancer, cardiovascular diseases and neurodegenerative diseases. Many efforts have been made to unravel the molecular mechanisms and the specific interactions of phytochemicals, which targets disease pathways in the AD. Further studies on these natural products and their mechanism of action, target specific effect in disease pathology parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine in treatment of AD. This review presents detailed information on natural products like polyphenols, alkaloids and terpenes with their potential effects in Alzheimer’s disease.

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Synthesis of New Quinoline-Piperonal Hybrids as Potential Drugs against Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20163944 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3944 ◽

Cited By ~ 3

Author(s):

Juliana de Oliveira C. Brum ◽

Denise Cristian F. Neto ◽

Joyce Sobreiro F. D. de Almeida ◽

Josélia Alencar Lima ◽

Kamil Kuca ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Theoretical Analysis ◽

Blood Brain Barrier ◽

Docking Studies ◽

New Drugs ◽

Brain Barrier ◽

Inhibitory Capacity ◽

Blood Brain ◽

Inhibitory Activities

Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer’s disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood–brain barrier, qualifying as leads for new drugs against AD. Evaluation of their inhibitory capacity against acetyl- and butyrilcholinesterases (AChE and BChE) through Ellmann’s test showed that three compounds present promising results with one of them being capable of inhibiting both enzymes. Further docking studies of the six compounds synthesized helped to elucidate the main interactions that may be responsible for the inhibitory activities observed.

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