Naturally Inspired Pyrimidines Analogues for Alzheimer’s Disease

: 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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Ketogenic Diet in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20163892 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3892 ◽

Cited By ~ 24

Author(s):

Marta Rusek ◽

Ryszard Pluta ◽

Marzena Ułamek-Kozioł ◽

Stanisław J. Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ketogenic Diet ◽

Neurodegenerative Disorder ◽

Ketone Bodies ◽

Amyloid Β ◽

The Body ◽

Aging Brain ◽

Effective Prevention ◽

Low Carbohydrate Diet

At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gained interest as a potential therapy for neurodegenerative disorders like Alzheimer’s disease. This review aims to examine the role of the ketogenic diet in Alzheimer’s disease progression and to outline specific aspects of the nutritional profile providing a rationale for the implementation of dietary interventions as a therapeutic strategy for Alzheimer’s disease.

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

Medicinal Chemistry ◽

10.2174/1573406415666190716115524 ◽

2020 ◽

Vol 16 (7) ◽

pp. 947-957

Author(s):

Maja Przybyłowska ◽

Iwona Inkielewicz-Stepniak ◽

Szymon Kowalski ◽

Krystyna Dzierzbicka ◽

Sebastian Demkowicz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sodium Iodide ◽

31P Nmr ◽

Neurodegenerative Disorder ◽

Docking Studies ◽

New Drugs ◽

Binding Ability ◽

Electric Eel ◽

Cholinesterase Inhibitory Activity

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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Az Alzheimer-kór heterogenitása

Orvosi Hetilap ◽

10.1556/650.2021.32130 ◽

2021 ◽

Vol 162 (25) ◽

pp. 970-977 ◽

Cited By ~ 1

Author(s):

Nóra Balázs ◽

Tibor Kovács

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Clinical Manifestations ◽

Symptomatic Therapy ◽

Significant Progress ◽

The Past ◽

Atypical Manifestations ◽

Recent Classification ◽

Made In

Összefoglaló. A neurodegeneratív betegségek között az Alzheimer-kór a leggyakoribb kórforma. Morbiditása és mortalitása világszerte egyre gyorsabb ütemben növekszik, ezáltal szociális és gazdasági hatása is folyamatosan fokozódó terhet jelent a társadalomra. Az elmúlt néhány évtizedben jelentős előrelépés történt az Alzheimer-kór megismerésében, számos biomarker támogatja a diagnózis felállítását, tüneti terápiát szolgáló gyógyszerek kerültek bevezetésre. Az Alzheimer-kór klinikai megjelenése, lefolyása, viselkedése rendkívül változatos képet mutat, felismerése a rendelkezésre álló eszközök ellenére is kihívást jelenthet a nagy tapasztalattal bíró klinikusok számára is. Munkánk céljául tűztük ki, hogy összefoglaljuk az Alzheimer-kór genetikai, patológiai és klinikai jellemzőit, segítve ezzel a betegség jobb meg- és felismerését. Bemutatjuk a jelenleg érvényben lévő patológiai és klinikai irányelvek kritériumrendszereit, az újabb klasszifikációs szemléleteket. Részletesen ismertetjük az Alzheimer-kór heterogenitását genotípus és fenotípus szintjén egyaránt. Elemezzük a típusos és atípusos megjelenési formák jellemzőit, a társuló kórállapotoknak a megjelenésre és a progresszióra gyakorolt hatását. Orv Hetil. 2021; 162(25): 970–977. Summary. Alzheimer’s disease is the most prevalent neurodegenerative disorder. Morbidity and mortality of Alzheimer’s disease are increasing worldwide causing important social and economic burden on the society. Over the past few decades, significant progress has been made in the understanding of the pathogenesis of Alzheimer’s disease, several biomarkers support the diagnosis and drugs for symptomatic therapy had been introduced. The clinical manifestations and the course of Alzheimer’s disease have a variable picture, so – despite the diagnostic opportunities – its diagnosis could be a challenge for highly experienced clinicians as well. The aim of our work was to summarize the genetic, pathological and clinical characteristics of Alzheimer’s disease, thus helping to better understand and recognize the disease. We present the criteria systems of the currently valid pathological and clinical guidelines with the most recent classification approaches. The heterogeneity of Alzheimer’s disease at both genotype and phenotype levels is described in detail. The characteristics of typical and atypical manifestations and the effect of co-pathologies on the appearance and progression of Alzheimer’s disease are also discussed. Orv Hetil. 2021; 162(25): 970–977.

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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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An Overview of Experimental and Clinical Spinal Cord Findings in Alzheimer’s Disease

Brain Sciences ◽

10.3390/brainsci9070168 ◽

2019 ◽

Vol 9 (7) ◽

pp. 168 ◽

Cited By ~ 1

Author(s):

Qing Xie ◽

Wei-Jiang Zhao ◽

Guan-Yong Ou ◽

Wei-Kang Xue

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Spinal Cord ◽

Nervous System ◽

Neurodegenerative Disorder ◽

The Elderly ◽

The Body ◽

Life Stages ◽

The Central Nervous System ◽

The Brain

Alzheimer’s disease (AD) is a neurodegenerative disorder that occurs mainly in the elderly and presenile life stages. It is estimated that by the year 2050, 135 million people will be affected by AD worldwide, representing a huge burden to society. The pathological hallmarks of AD mainly include intracellular neurofibrillary tangles (NFTs) caused by hyperphosphorylation of tau protein, formation of extracellular amyloid plaques, and massive neural cell death in the affected nervous system. The pathogenesis of AD is very complicated, and recent scientific research on AD is mainly concentrated on the cortex and hippocampus. Although the spinal cord is a pivotal part of the central nervous system, there are a limited number of studies focusing on the spinal cord. As an extension of the brain, the spinal cord functions as the bridge between the brain and various parts of the body. However, pathological changes in the spinal cord in AD have not been comprehensively and systematically studied at present. We here review the existing progress on the pathological features of AD in the spinal cord.

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

BioMed Research International ◽

10.1155/2021/1280237 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Negar Sadat Soleimani Zakeri ◽

Saeid Pashazadeh ◽

Habib MotieGhader

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Interaction ◽

Target Genes ◽

Neurodegenerative Disorder ◽

Gentian Violet ◽

New Drugs ◽

Medical Studies ◽

Protein Protein Interaction ◽

Gene Complexes

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 are vital. This study proposes a method to extract substantial gene complexes and then introduces potential drugs in Alzheimer’s disease. To this end, a protein-protein interaction (PPI) network was utilized to extract five meaningful gene complexes functionally interconnected. An enrichment analysis to introduce the most important biological processes and pathways was accomplished on the obtained genes. The next step is extracting the drugs related to AD and introducing some new drugs which may be helpful for this disease. Finally, a complete network including all the genes associated with each gene complex group and genes’ target drug was illustrated. For validating the proposed potential drugs, Connectivity Map (CMAP) analysis was accomplished to determine target genes that are up- or downregulated by proposed drugs. Medical studies and publications were analyzed thoroughly to introduce AD-related drugs. 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 and 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. Besides the primary goal, five bipartite networks representing the genes of each group and their target miRNAs were constructed to introduce target miRNAs.

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