scholarly journals Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6015
Author(s):  
Beatrice Bargagna ◽  
Lidia Ciccone ◽  
Susanna Nencetti ◽  
M. Amélia Santos ◽  
Sílvia Chaves ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ferulic Acid ◽  
Neurodegenerative Disorder ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Biological Evaluation ◽  
Oral Drugs ◽  
Pharmacokinetic Properties ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.

Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey

2020 ◽  
Vol 18 (4) ◽  
pp. 354-359
Author(s):  
Shirin Tarbiat ◽  
Azize Simay Türütoğlu ◽  
Merve Ekingen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Acetylcholinesterase Activity ◽  
Rosa Damascena ◽  
Free Radical Damage

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impairment of language. Alzheimer's disease is strongly associated with oxidative stress and impairment in the cholinergic pathway, which results in decreased levels of acetylcholine in certain areas of the brain. Hence, inhibition of acetylcholinesterase activity has been recognized as an acceptable treatment against Alzheimer's disease. Nature provides an array of bioactive compounds, which may protect against free radical damage and inhibit acetylcholinesterase activity. This study compares the in vitro antioxidant and anticholinesterase activities of hydroalcoholic extracts of five cultivars of Rosa Damascena Mill. petals (R. damascena 'Bulgarica', R. damascena 'Faik', R. damascena 'Iranica', R. damascena 'Complex-635' and R. damascena 'Complex-637') from Isparta, Turkey. The antioxidant activities of the hydroalcoholic extracts were tested for ferric ion reduction and DPPH radical scavenging activities. The anti-acetylcholinesterase activity was also evaluated. All rose cultivars showed a high potency for scavenging free radical and inhibiting acetylcholinesterase activity. There was a significant correlation between antioxidant and acetylcholinesterase inhibitory activity. Among cultivars, Complex-635 showed the highest inhibitory effect with an IC50 value of 3.92 µg/mL. Our results suggest that all these extracts may have the potential to treat Alzheimer's disease with Complex-635 showing more promise.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals In Silico Molecular Docking Approach Against Enzymes Causing Alzheimer’s Disease Using Borassus Flabellifer Linn

2021 ◽  
Author(s):  
Jason Tom Abraham ◽  
H. Noorul Samsoon Maharifa ◽  
S Hemalatha
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Affinity ◽  
Neurodegenerative Disorder ◽  
Natural Compounds ◽  
Live Cells ◽  
Synergistic Activity ◽  
Pharmacokinetic Properties ◽  
Docking Approach ◽  
Life Threatening

Abstract Alzheimer’s disease is a life-threatening neurodegenerative disorder. About 50 million people across the globe are affected by this disease. At final stages, this disease causes patients to lose cognitive ability, memory and brain cells to the point of being totally depend on other individuals for livelihood. The incidence of this disease is increasing across the world in the recent years, making the need of a better drug an urgency. Existing drugs show various side-effects and natural sources of medicinal drugs are being explored. In this study, we explore the activity of natural compounds isolated through GCMS analysis from the haustoria of palmyra palm against two major Alzheimer’s disease-causing enzymes, β-amyloid and Acetylcholinesterase. The binding affinity of these compounds against the target proteins and their pharmacokinetic properties were checked. Among the 37 compounds docked, 5 compounds showed good binding affinity and pharmacokinetic properties. These natural compounds showed a potential as a drug against Alzheimer’s disease. Further research is needed to study the synergistic activity of the compounds in live cells.

2D- and 3D-QSAR Modeling of Imidazole-Based Glutaminyl Cyclase Inhibitors

2019 ◽  
Vol 15 ◽  
Author(s):  
Omar Husham Ahmed Al-Attraqchi ◽  
Katharigatta N. Venugopala
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Neurodegenerative Disorder ◽  
3D Qsar ◽  
Biological Evaluation ◽  
Qsar Modeling ◽  
Glutaminyl Cyclase ◽  
Validation Parameters ◽  
Qsar Models

Background: Glutaminyl cyclase (QC) is a novel target in the battle against Alzheimer’s disease, a highly prevalent neurodegenerative disorder. QC inhibitors have the potential to be developed as therapeutically useful anti-Alzheimer’s disease agents. Methods: Linear and non-linear 2D-quantitative structure–activity relationship (QSAR) models were developed using stepwise-multiple linear regression (S-MLR) and neural networks. Partial least squares (PLS) method was used to develop a 3D-QSAR model. Also, the developed models were used in a virtual screening of the ZINC database to identify potential QC inhibitors. Results: The 2D neural network model showed superior predictive ability, as demonstrated by the validation parameters R2 = 0.933, Q2 = 0.886 and R2pred = 0.911. The 3D-QSAR model’s steric and electrostatic fields’ isocontour maps were visualized and revealed important structural requirements associated with good activity. The virtual screening identified six compounds as potentially active QC inhibitors with improved pharmacokinetic profiles. Conclusion: The developed QSAR models can be used to predict the activity of compounds not yet synthesized and prioritize their synthesis and biological evaluation. Also, potentially active QC inhibitors have been identified with attractive lead-like properties that can be used to develop anti-Alzheimer’s disease agents.

scholarly journals Synthesis and Biological Evaluation of New Cholinesterase Inhibitors for Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2033 ◽  
Author(s):  
Weiam Hussein ◽  
Begüm Sağlık ◽  
Serkan Levent ◽  
Büşra Korkut ◽  
Sinem Ilgın ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
The Elderly ◽  
Docking Study ◽  
Biological Evaluation ◽  
Cytotoxicity Test ◽  
Synthesis And Biological Evaluation ◽  
The Brain ◽  
Che Inhibitors

Alzheimer’s disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD.

scholarly journals Association of Serum Uric Acid level in Patients with Alzheimer’s Disease

2017 ◽  
Vol 33 (2) ◽  
pp. 83-88
Author(s):  
Mohammad Saifullah Ahtesam ◽  
Md Ahsan Habib ◽  
Md Rafiqul Islam ◽  
Md Rezaul Karim Khan ◽  
Hasan Zahidur Rahman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Uric Acid ◽  
Serum Uric Acid ◽  
Uric Acid Level ◽  
Acid Level ◽  
Serum Uric Acid Level ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Control Group

Background: Alzheimer’s disease is the most common cause of dementia. Uric acid is the end product of purine metabolism in humans and acts as a natural antioxidant, accounting up to 60% of the free radical scavenging activity in human blood to prevent free radicals induced oxidative cell injury. This study aimed to explore the association between serum uric acid level and cognitive impairment of Alzheimer’s disease patients compared to those of the non-demented age and sex matched controls. Methods: This case control study was carried out in the department of neurology, BSMMU, Dhaka. Total 116 patients were enrolled as study population after satisfying inclusion and exclusion criteria. Among them, 58 were grouped as case and rest 58 were control. All blood samples for serum uric acid were measured in the Biochemistry lab, Department of Biochemistry, BSMMU, Dhaka. Results: A signiûcant reduction of serum uric acid levels in the AD group was found compared to those of the control group (4.35±1.59 Vs 6.89±1.68) which was statistically significant (p<0.001). We also found a positive correlation between serum uric acid levels with severity of Alzheimer’s disease (rp = 0.633, P<0.001). Among demographic variables educational qualification was statistically significant (p=0.006) in AD patients. Conclusion: This study showed that oxidative injuries have an important role in the pathogenesis of AD. Higher levels of uric acid are associated with a decreased risk of dementia and better cognitive function later in life. Bangladesh Journal of Neuroscience 2017; Vol. 33 (2): 83-88

scholarly journals Monoclonal antibodies in the treatment of Alzheimer’s disease: a literature review

2021 ◽  
Author(s):  
Pedro Henrique Carvalho Furtado de Mendonça ◽  
Fernanda Rabello Detoni ◽  
Letícia Silva Brandão dos Santos ◽  
Talita Cardoso Gomes ◽  
Ivan Magalhães Viana
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoclonal Antibodies ◽  
Neurodegenerative Disorder ◽  
Controlled Trial ◽  
Test Group ◽  
Pubmed Database ◽  
Significant Difference ◽  
Collateral Effects ◽  
Aβ Aggregation

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder, whose treatment is limited to drugs that offer comfort to the patient. Immunotherapy with monoclonal antibodies (mAbs) has been the subject of a study with the promise of reversing cognitive deficits. In this scenario, we conducted a systematic review to elucidate aspects about the effectiveness of such treatment. Objectives: Analyze the prognostic of patients with AD through immunotherapy using anti-amilody mAbs. Methods: It was used the PubMed database using the descriptors: “Amyloid beta-Peptides AND Alzheimer disease AND Immunotherapy”. Filters: clinical trial, randomized controlled trial. 6 articles from 2015 to 2021 were selected. Inclusion criteria: (1) mAbs as treatment for AD; (2) Analyze the prognostic. Results: The immunotherapy with bapineuzumab and solanezumab didn’t showed no statistically significant difference between the groups of bapineuzumab 0,5 mg / kg (p = 0,979) and placebo (p = 0,973) and a change of 6.65 in the solanezumab group and 7.44 in the placebo group (difference, −0.80; P = 0 , 10). However, subcutaneous treatment of bapineuzumab exhibited fewer abnormalities of images related to amyloid with edema or effusion (AIRA), so, better tolerated compared to intravenous treatment. In the study with the ABvac40 vaccine, about 92% of the individuals in the test group developed specific anti-Aβ 40 antibodies. Conclusion: Bapineuzumab and solanezumab didn’t achieve significant results in the reduction of cognitive decline, however bapineuzumab enabled the prevention of Aβ aggregation. However, the use of mAbs can trigger collateral effects, requiring an individual analysis.

scholarly journals Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-target Agents for the Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3100 ◽  
Author(s):  
Xiao-Qin Wang ◽  
Chu-Ping Zhao ◽  
Long-Cheng Zhong ◽  
De-Ling Zhu ◽  
De-Hao Mai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Aged People ◽  
Structure Activity ◽  
Aβ Aggregation ◽  
Aggregation Inhibition ◽  
Low Toxicity ◽  
Multifunctional Agents

Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ1–42 aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a N,N-dimethylaminoalkylamino moiety at the 4-position increased the Aβ1–42 aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound 6b1, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu2+-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ1–42 aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound 6b1 showed low toxicity and a good neuroprotective effect against Aβ1–42-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound 6b1 significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound 6b1 was a promising multi-target compound worthy of further study for AD.

scholarly journals Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3165
Author(s):  
Matheus de Freitas Silva ◽  
Ellen Tardelli Lima ◽  
Letizia Pruccoli ◽  
Newton Castro ◽  
Marcos Guimarães ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Activity ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Acyl Hydrazone ◽  
New Compounds ◽  
Further Development

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aβ42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.

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