Imidazole: Multi-targeted Therapeutic Leads for the Management of Alzheimer’s Disease

2022 ◽  
Vol 22 ◽  
Author(s):  
Ashwani K. Dhingra ◽  
Bhawna Chopra ◽  
Akash Jain ◽  
Jasmine Chaudhary
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ion ◽  
Acetylcholinesterase Inhibitors ◽  
Drug Candidates ◽  
The Status ◽  
Aβ Aggregation ◽  
Neuro Inflammation ◽  
Therapeutic Leads ◽  
Novel Drug

Background: Alzheimer's disease (AD) is a multifactorial disorder coupled with an array of neuropathological mechanisms, including tau phosphorylation, Aβ aggregation, metal ion deregulation, and oxidative stress, along with neuro-inflammation. The clinically available drugs for the management of AD include four acetylcholinesterase inhibitors and one glutamatergic antagonist. These agents provide only temporary relief from the symptoms by altering the neurotransmitter level in the brain. Objective: Keeping in view the focus on research, the numerous pharmacological activities associated with the aromatic diazole heterocyclic nucleus, imidazole, triggered the medicinal chemist to develop a large number of novel anti-AD compounds targeting multiple pathological mechanisms associated with AD. These prepared analogs represent a higher potential against neurological disorders, including AD. This review article aims an ornately pronounce the therapeutic voyage of imidazole and its analogs as anti-AD. Method: It emphasizes the synthesized imidazole derivatives as anti–AD with multiple targets reviewed from the data available on Pubmed. Result: These compounds diminish the pathophysiological aspects of AD; still, further studies are required to prove the safety and efficacy of these compounds in humans. Conclusion: The review aims to provide knowledge and highlight the status of this moiety in the design and development of novel drug candidates against Alzheimer’s disease conditions. Thus, it paves the way for further work.

scholarly journals Full-length and C-terminal neurogranin in Alzheimer’s disease cerebrospinal fluid analyzed by novel ultrasensitive immunoassays

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Annika Öhrfelt ◽  
Julien Dumurgier ◽  
Henrik Zetterberg ◽  
Agathe Vrillon ◽  
Nicholas J. Ashton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Full Length ◽  
The Novel ◽  
Drug Candidates ◽  
Postsynaptic Protein ◽  
Coefficients Of Variation ◽  
Assay Precision ◽  
Novel Drug

Abstract Background Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer’s disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease. Methods In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26). Results The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785). Conclusions Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.

scholarly journals Potential Therapeutic Strategies for Alzheimer’s Disease Targeting or Beyondβ-Amyloid: Insights from Clinical Trials

2014 ◽  
Vol 2014 ◽  
pp. 1-22 ◽  
Author(s):  
Qiutian Jia ◽  
Yulin Deng ◽  
Hong Qing
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Targets ◽  
Neurodegenerative Disorder ◽  
Therapeutic Strategies ◽  
Therapeutic Approaches ◽  
Drug Candidates ◽  
Effective Drugs ◽  
Novel Drug

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with two hallmarks:β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer’s disease.

Screening novel drug candidates for Alzheimer’s disease by an integrated network and transcriptome analysis

2020 ◽  
Vol 36 (17) ◽  
pp. 4626-4632
Author(s):  
Yonglin Peng ◽  
Meng Yuan ◽  
Juncai Xin ◽  
Xinhua Liu ◽  
Ju Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Supplementary Information ◽  
Integrated Network ◽  
Drug Candidates ◽  
Novel Drug

Abstract Motivation Alzheimer’s disease (AD) is a serious degenerative brain disease and the most common cause of dementia. The current available drugs for AD provide symptomatic benefit, but there is no effective drug to cure the disease. The emergence of large-scale genomic, pharmacological data provides new opportunities for drug discovery and drug repositioning as a promising strategy in searching novel drug for AD. Results In this study, we took advantage of our increasing understanding based on systems biology approaches on the pathway and network levels and perturbation datasets from the Library of Integrated Network-Based Cellular Signatures to introduce a systematic computational process to discover new drugs implicated in AD. First, we collected 561 genes that have reported to be risk genes of AD, and applied functional enrichment analysis on these genes. Then, by quantifying proximity between 5595 molecule drugs and AD based on human interactome, we filtered out 1092 drugs that were proximal to the disease. We further performed an Inverted Gene Set Enrichment analysis on these drug candidates, which allowed us to estimate effect of perturbations on gene expression and identify 24 potential drug candidates for AD treatment. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a useful systematic method, our approach can also be used to identify efficacious therapies for other complex diseases. Availability and implementation The source code is available at https://github.com/zer0o0/drug-repo.git. Supplementary information Supplementary data are available at Bioinformatics online.

GSK-3 Inhibitors: A new class of drugs for Alzheimer's Disease Treatment

2021 ◽  
Vol 22 ◽  
Author(s):  
Dilipkumar Pal ◽  
Souvik Mukherjee ◽  
In-ho Song ◽  
Satish Balasaheb Nimse
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Proteins ◽  
Drug Candidates ◽  
New Class ◽  
Drug Molecules ◽  
Function Impairment ◽  
Relationship Of ◽  
Novel Drug

: Alzheimer's disease (AD), a chronic neurodegenerative disease, is the most common form of dementia that causes cognitive function impairment, including memory, thinking, and behavioral changes that ultimately lead to death. The over activation of GSK-3, an enzyme from the proline/serine Ki NS family, has been associated with hyper-phosphorylation of tau proteins. Hyper-phosphorylated tau proteins self-assemble to form tangles of straight and helical filaments are known to be involved in AD. Therefore, GSK-3 has been considered a potential target of novel drug discovery for AD treatment. The research on the development of GSK-3 inhibitors has received enormous attention from the vast scientific community because they are targeted for AD and other diseases, including type 2 diabetes, cancers, stroke, Parkinson's disease, bipolar disorder etc. Various drugs originated from synthetic and natural origins have been designed to inhibit GSK-3 activity. However, there is a need to develop novel drug candidates that are selective in the inhibition of GSK3. Hence, this review summarizes the potential of GSK-3 inhibitors for AD therapy. The structure-activity relationship of current drug molecules and the potential problems associated with them are discussed in detail.

A Nanoinformatics Approach to Evaluate the Pharmacological Properties of Nanoparticles for the treatment of Alzheimer’s Disease

2021 ◽  
Vol 24 ◽  
Author(s):  
Muhammad Zohaib Nawaz ◽  
Syed Awais Attique ◽  
Qurat-ul-Ain ◽  
Fahdah Ayed Alshammari ◽  
Heba Waheeb Alhamdi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Carbon Nanotubes ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Drug Targets ◽  
Kinase Domain ◽  
New Drugs ◽  
Drug Candidates ◽  
Experimental Approaches ◽  
Novel Drug

Background: Alzheimer’s disease is a nervous system destructive disease which causes structural, biochemical and electrical abnormalities inside the human brain and results due to genetic and various environmental factors. Traditional therapeutic agents of Alzheimer’s disease such as tacrine and physostigmine has been found causing adverse effects to the nervous system and gastrointestinal tract. Nanomaterials like graphene, metals, carbon-nanotubes and metal-oxides are gaining attention as potential drugs against Alzheimer’s disease due to their properties such as large surface area which provides clinical efficiency, targeted drug designing and delivery. Objectives: Designing new drugs by using experimental approaches are time-consuming, tedious and laborious processes which also require advanced technologies. This study aims to identify the novel drug candidates against Alzheimer’s disease with no or less associated side effects using molecular docking approaches. Methods: In this study, we utilized nanoinformatics based approaches for evaluating the interaction properties of various nanomaterials and metal nanoparticles with the drug targets including TRKB kinase domain, EphA4 and histone deacetylase. Furthermore, drug-likeness of carbon nanotubes was confirmed through ADME analysis. Results: Carbon nanotubes, either single or double-walled in all the three-configuration including zigzag, chiral, and armchair forms are found to interact with the target receptors with varying affinities. Conclusion: This study provides a novel and clearer insights into the interaction properties and drug suitability of known putative nanoparticles as potential agents for the treatment of Alzheimer’s disease.

scholarly journals Novel drug candidates targeting Alzheimer’s disease: ethical challenges with identifying the relevant patient population

2021 ◽  
pp. medethics-2021-107304
Author(s):  
Erik Gustavsson ◽  
Pauline Raaschou ◽  
Gerd Lärfars ◽  
Lars Sandman ◽  
Niklas Juth
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Risk Stratification ◽  
New Drugs ◽  
Ethical Challenges ◽  
Cascade Screening ◽  
Drug Candidates ◽  
Novel Drug ◽  
Current Risk

Intensive research is carried out to develop a disease-modifying drug for Alzheimer’s disease (AD). The development of drug candidates that reduce Aß or tau in the brain seems particularly promising. However, these drugs target people at risk for AD, who must be identified before they have any, or only moderate, symptoms associated with the disease. There are different strategies that may be used to identify these individuals (eg, population screening, cascade screening, etc). Each of these strategies raises different ethical challenges. In this paper, we analyse these challenges in relation to the risk stratification for AD necessary for using these drugs. We conclude that the new drugs must generate large health benefits for people at risk of developing AD to justify the ethical costs associated with current risk stratification methods, benefits much larger than current drug candidates have. This conclusion raises a new set of ethical questions that should be further discussed.

scholarly journals Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 4005
Author(s):  
Giambattista Marotta ◽  
Filippo Basagni ◽  
Michela Rosini ◽  
Anna Minarini
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Symptomatic Relief ◽  
Acetylcholinesterase Inhibitors ◽  
Neurotransmitter System ◽  
Antioxidant Agents ◽  
Aβ Aggregation ◽  
Aggregation Inhibitors ◽  
Orally Active ◽  
Directed Structure

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

Understanding the Binding Mechanism of Amyloid-β Inhibitors from Molecular Simulations

2018 ◽  
Vol 24 (28) ◽  
pp. 3341-3346
Author(s):  
Linh Tran
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Specific Binding ◽  
Amyloid Β ◽  
Random Coil ◽  
Binding Mechanism ◽  
Drug Candidates ◽  
Aβ Aggregation ◽  
Potential Inhibitors

In recent years, Aβ aggregation prevention, one of the most concerned strategies in drug development has been carefully assessed to treat Alzheimer’s disease. Aβ peptides can transform structurally from random coil monomer into β-stranded protofibril via multiple oligomeric states. Among the various Aβ species, the identification of binding targets has been challenging due to the heterogeneity and metastable nature. A better understanding of Aβ species’ assembly details and structural properties has been more characterized recently. Numerous potential inhibitors have been identified that they can effectively bind to different Aβ species such as monomer, oligomer or protofibril during the inhibition of Aβ aggregation process. This review highlights the diversity of structural ensembles of Aβ species, from monomer to protofibril forms and the specific binding targets by their potential inhibitors. Comprehending the binding mechanism of Aβ inhibitors is indispensable for searching novel drug candidates against early-stage Alzheimer’s disease.

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