Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents

Luo, Wen; Wang, Ting; Chen, Hong; Yang, Ya‐Chen; Chen, Ying; Cen, Juan; Xie, Songqiang; Wang, Chao–Jie

doi:10.1016/j.ejmech.2016.06.022

Cited by 44 publications

(17 citation statements)

References 22 publications

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“…In our early efforts to identify novel AChE inhibitors, hesperitin was identified as an AChE inhibitor with an IC 50 value of 1.02 μM. On the basis of the dual-site strategy that was designed according to the structural characteristics of hesperitin and the benzene or heteroaromatic ring side chain structure of AChE inhibitors [ 22 ], we designed a dual-site AChE inhibitor that acts on both the AChE central CAS and PAS with the benzene or heteroaromatic ring terminal side chain structure as the parent ( Scheme 1 ). We wanted to synthesize the hesperitin derivatives where part 1 can binds to the PAS and part 2 can bind to the CAS.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents

Huang

Zhang

et al. 2017

Molecules

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In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced β-amyloid (Aβ) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents

Huang

Zhang

et al. 2017

Molecules

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“…An estimated 115 million patients will be diagnosed with AD by 2050. These AD patients will progress to dementia within 5 years of diagnosis and will account for approximately half of all dementia cases (Luo et al, 2016). The typical pathogenesis of AD is the accumulation of amyloid-β (Aβ) aggregates, and the hyperphosphorylation of the tau proteins, which together lead to neurofibrillary tangles (NFTs) and synaptic dysfunction (Wallace and Dalton, 2011;Asaad and Lee, 2018).…”

Section: Introductionmentioning

confidence: 99%

Network Pharmacology-Based and Experimental Identification of the Effects of Quercetin on Alzheimer’s Disease

Qi¹,

Gao

et al. 2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) is one of the neurodegenerative brain disorders inducing nearly half of dementia cases, and the diagnosis and treatment of AD are the primary issues clinically. However, there is a lack of effective biomarkers and drugs for AD diagnosis and therapeutics so far. In this study, bioinformatics analysis combined with an experimental verification strategy was used to identify the biomarkers and the quercetin targets for AD diagnosis and treatment. First, differentially expressed genes in the AD brain were identified by microarray data analysis. Second, quercetin, a predominant flavonoid, was used to screen the target genes. Third, the drug-disease network was determined, and the target genes of quercetin treatment were obtained in AD-related HT-22 cellbased assay. Six genes, including MAPT, PIK3R1, CASP8, DAPK1, MAPK1, and CYCS, were validated by the system pharmacology analysis in the hippocampus samples of AD patients. The results suggested that MAPT, PIK3R1, CASP8, and DAPK1 were significantly increased, but MAPK1 and CYCS were significantly decreased in HT-22 cells after Aβ1-42 treatment. Moreover, MAPK1 and CYCS were markedly increased, but MAPT, PIK3R1, CASP8, and DAPK1 were markedly decreased after quercetin treatment in these HT-22 cells. Altogether, MAPT, PIK3R1, CASP8, DAPK1, MAPK1, and CYCS are all the biomarkers for AD diagnosis and the targets of quercetin treatment, and our findings may provide valuable biomarkers for AD diagnosis and treatment.

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“…As a multifaceted neurodegenerative disorder, Alzheimer's disease (AD) greatly impacts the health of the affected elderly population (1). However, the pathophysiology of AD has not been completely elucidated to date.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of acetylcholinesterase activity and β‑amyloid oligomer formation by 6‑bromotryptamine�A, a multi‑target anti‑Alzheimer's molecule

et al. 2019

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by learning and memory impairments. Recent studies have suggested that AD can be induced by multiple factors, such as cholinergic system dysfunction and β-amyloid (Aβ) neurotoxicity. It was reported that 6-bromo-N-propionyltryptamine could treat neurological diseases, including AD. In the present study, 6-bromotryptamine A, a derivative of 6-bromo-N-propionyltryptamine, was synthesized by the condensation of 2-(6-bromo-1H-indol-3-yl)ethan-1-amine and 2-(4-bromophenyl)acetic acid, and was used as a potential anti-AD molecule. Furthermore, scopolamine can induce impairments of learning and memory, and was widely used to establish AD animal models. The results demonstrated that 6-bromotryptamine A significantly prevented scopolamine-induced short-term cognitive impairments, as revealed by various behavioral tests in mice. Furthermore, an acetylcholinesterase (AChE) activity assay revealed that 6-bromotryptamine A directly inhibited AChE activity. Notably, it was observed that 6-bromotryptamine A blocked the formation of Aβ oligomer, as evaluated by the dot blot assay. All these results suggested that 6-bromotryptamine A may be used to prevent impairments in short-term learning and memory ability possibly via the inhibition of AChE and the blockade of Aβ oligomer formation.

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Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents

Cited by 44 publications

References 22 publications

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents

Network Pharmacology-Based and Experimental Identification of the Effects of Quercetin on Alzheimer’s Disease

Inhibition of acetylcholinesterase activity and β‑amyloid oligomer formation by 6‑bromotryptamine�A, a multi‑target anti‑Alzheimer's molecule

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