PYRAZOLINE CONTAINING MOLECULES AS MULTIFUNCTIONAL AGENTS IN ALZHEIMER’S DISEASE

INDIAN DRUGS ◽  
2019 ◽  
Vol 56 (10) ◽  
pp. 22-25
Author(s):  
M Khambete ◽  
P. Murumkar ◽  
A Kumar ◽  
T. Darreh-Shori ◽  
S. De ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
The Past ◽  
Glycation End Products ◽  
Aβ Aggregation ◽  
Aggregation Inhibition ◽  
Multifunctional Agents ◽  
Β Amyloid ◽  
Multifunctional Molecules

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease which is caused mainly due to accumulation of an aberrant protein known as β-amyloid in the form of senile plaques. However, over the past few years, network biology studies have indicated that classical “one drug-one target” hypothesis may not work in diseases such as AD where the biochemical disease mechanisms are intricately interconnected. therefore, multifunctional molecules which can modulate several targets could be the key towards finding the therapeutics for this debilitating disorder. Keeping this in mind, several pyrazoline containing molecules with promising Aβ aggregation inhibition potential were explored further against key targets involved in AD, such as cholinesterases, oxidative stress and advanced glycation end products (AGe). Some potential multifunctional molecules were identified as a result of this work.

scholarly journals Tocotrienol decreases β-amyloid mediated toxicity in Caenorhabditis elegans model of Alzheimer’s disease

2020 ◽  
Author(s):  
Chee Wah Yuen ◽  
Mardani Abdul Halim ◽  
Vikneswaran Murugaiyah ◽  
Nazalan Najimudin ◽  
Ghows Azzam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Senile Plaques ◽  
Amyloid Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
Anti Oxidant ◽  
Β Amyloid ◽  
Β Amyloid Peptide

AbstractAlzheimer’s disease (AD) is a neurological disease caused by the accumulation of extracellular senile plaques consisting of β-amyloid peptide (Aβ) in the brain. A transgenic Caenorhabditis elegans which demonstrated paralysis due to the expression of human beta amyloid Aβ42 gene was used to study the anti-paralysis effect of mixed tocotrienols. The content of the mixed tocotrienols were 12.1% α-, 2.7% β-, 18.6% γ-, and 8.1% δ-tocotrienols. Mixed tocotrienols significantly delayed the Aβ-induced paralysis in the transgenic nematode and exhibited anti-oxidant properties towards Aβ-generated oxidative stress. The mixture also presented potent inhibitory activities against Aβ aggregation with an IC50 value of 600 ng/ml. It is concluded that mixed tocotrienols could potentially serve as a new therapeutic candidate for AD.

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 and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

2020 ◽  
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 ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Aggregation Inhibition ◽  
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 were evaluated including acetylcholinesterase (AChE), butylcholinesterase (BuChE), and Aβ1−42 aggregation inhibition as well as neuroprotective effects and metal-chelating properties. The results indicated highly selective BuChE inhibitory activity with IC50 values of 21.71 µM for compound 10 h as the most potent compound. Besides, compound 10 h could inhibit self-induced Aβ1−42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition value, respectively. A Lineweaver–Burk plot and molecular modeling study also showed that compound 10 h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10 h was potent as a selective Cu2+ chelator. Thus, the designed scaffold could be considered as multifunctional agents for AD drug discovery developments.

Biological Signatures of Alzheimer’s Disease

2020 ◽  
Vol 20 (9) ◽  
pp. 770-781 ◽  
Author(s):  
Poornima Sharma ◽  
Anjali Sharma ◽  
Faizana Fayaz ◽  
Sharad Wakode ◽  
Faheem H. Pottoo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Senile Plaque ◽  
Senile Plaques ◽  
Amyloid Deposition ◽  
Immune Defense ◽  
Amyloid Angiopathy ◽  
Microvascular Changes ◽  
Β Amyloid

Alzheimer’s disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer’s patients. It was seen that 70% of Alzheimer’s cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.

scholarly journals Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2182 ◽  
Author(s):  
Luca Piemontese ◽  
Gabriele Vitucci ◽  
Marco Catto ◽  
Antonio Laghezza ◽  
Filippo Perna ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Characteristics ◽  
Biological Properties ◽  
Cognitive Capacity ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Ad Therapy ◽  
Target Activity

A few symptomatic drugs are currently available for Alzheimer’s Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of β-amyloid (Aβ) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, 1 showed the best activity as an antioxidant (EC50 = 2.6 ± 0.2 μmol/µmol of DPPH) while compound 2 proved to be effective in the inhibition of AChE (IC50 = 6.86 ± 0.67 μM) and Aβ1–40 aggregation (IC50 = 74 ± 1 μM). Furthermore, compound 6 inhibited BChE (IC50 = 1.75 ± 0.59 μM) with a good selectivity toward AChE (IC50 = 86.0 ± 15.0 μM). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds 1, 3 and 4 and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).

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

BMC Chemistry ◽  
2020 ◽  
Vol 14 (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.

scholarly journals Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

2021 ◽  
Vol 7 (25) ◽  
pp. eabg4855
Author(s):  
Wojciech Michno ◽  
Katie M. Stringer ◽  
Thomas Enzlein ◽  
Melissa K. Passarelli ◽  
Stephane Escrig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mass Spectrometry Imaging ◽  
Isotope Labeling ◽  
Brain Regions ◽  
Plaque Development ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Detailed Picture

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer’s disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

Sign in / Sign up

Export Citation Format

Share Document