Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease

Wang, Dongmei; Hu, Min; Li, Xinpeng; Zhang, Dan; Chen, Chengjuan; Fu, Junmin; Shao, Shuai; Shi, Gaona; Zhou, Yu; Wu, Song; Zhang, Tiantai

doi:10.1016/j.ejmech.2019.02.053

Cited by 29 publications

(13 citation statements)

References 33 publications

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“…The in vivo study also confirmed that it did not induce acute toxicity even at high doses (1000 mg/kg), but penetrated through the BBB into the CNS and caused significant improvements in mice with scopolamine-induced cognitive deficit, which were revealed by passive avoidance test (58).…”

Section: Multifunctional Ligands Combining H 3 R Antagonism and Cholinesterase Inhibitionsupporting

confidence: 56%

Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Pasieka

Panek

Malawska

2020

Alzheimer’s Disease: Drug Discovery

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Alzheimer' s disease is a progressive, incurable, and complex neurodegenerative disease. Currently, an effective treatment that can slow down or stop the damage and death of neurons, which is a characteristic of Alzheimer' s disease, is lacking. Taking into account the complex nature of the disease, a multitarget design approach has been developed for the production of new potential anti-AD agents. The goal of this approach is to create a single molecule that can interact selectively with several desired molecular targets relevant to the disease. This strategy was successfully developed two decades ago and has been improved in recent years. This chapter describes the progress made in the discovery and design of selected multitargeted drugs based on molecular targets, which can be used for treating Alzheimer' s disease. The most promising among these drugs are the molecules having properties that are valuable not only in the symptomatic therapy but also in the causal treatment of the disease. The main hypotheses of Alzheimer' s disease, such as β-amyloid (Aβ), tau, and cholinergic, suggest that compounds capable of inhibiting the aggregation of neurotoxic Aβ-amyloid peptide and tau protein, and improving the cholinergic neurotransmission, may possess such properties.

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Section: Multifunctional Ligands Combining H 3 R Antagonism and Cholinesterase Inhibitionsupporting

confidence: 56%

Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Pasieka

Panek

Malawska

2020

Alzheimer’s Disease: Drug Discovery

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“…The relationship between neuroinflammation and neurodegenerative disorders including AD has been studied by many investigators and suggested that the molecular mechanism of AD pathophysiology on learning, memory and neuronal plasticity might occur under the influence of inflammation [22,23]. Much of the attention has been devoted to natural anti-inflammatory substances to improve the cognitive impairments in AD-like pathology [24,25]. TQ might be a strong candidate for preventing or delaying the symptoms of AD by reducing neurotoxicity via its anti-inflammatory activity [26].…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone (TQ) demonstrates its neuroprotective effect via an anti-inflammatory action on the Aβ_(1–42)-infused rat model of Alzheimer's disease

Elibol

Terzioglu-Usak

Beker

et al. 2019

Psychiatry and Clinical Psychopharmacology

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OBJECTIVES: Alzheimer's disease (AD) is a severe neurodegenerative disease with presentation of the neuronal death, memory loss and cognitive decline. The relationship between neuroinflammation and AD has been well documented. However, the options of antiinflammatory treatment are very limited in patients with AD. Previous studies showed that flavonoids might be an effective treatment and thymoquinone (TQ), an aromatic hydrocarbon found in Nigella sativa suggested as a candidate molecule due to having strong anti-inflammatory effects. Our study aimed to investigate the effects of TQ on neuroinflammation and neuroprotection in Aβ (1-42) infused rat model of AD. METHODS: A rat model of AD was established in 6 month-old rats (n = 23) by intra-hippocampal infusion during 14 days via a micro-osmotic pump containing aggregated Aβ (1-42) . After model establishment, TQ at a dosage of 20 mg/kg/day was intubated intragastrically for 15 days. The functional recovery was determined using the Morris Water Maze task by measuring memory consolidation. The content of cytokine levels of Tumour Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-1 alpha (IL-1α) and Interferon-gamma (IFN-γ) in the hippocampus was assessed by Magnetic Luminex assay. In order to reveal the functional molecular changes in hippocampal tissue upon TQ administration, the protein expression profile of neuronal migration protein Doublecortin (DCX), synaptic plasticity marker Mitogen Activated Protein Kinase2 (MAP2) and apoptosis related protein Poly (ADP-ribose) Polymerase (PARP) was analyzed by Western blotting. RESULTS: Aβ (1-42) infused group had worse memory performance than sham control group on Day 4 with an amelioration in this behaviour by TQ. In our study, the levels of TNF-α, IL-1α and IL-1β did not significantly alter among groups. On the other hand, Aβ (1-42) infusion slightly decreased the level of IFN-γ compared to sham control group. TQ treatment ameliorated both impaired memory performance and IFN-γ levels. It was found that TQ treatment increased the protein levels of DCX compared to the sham control group. Also, the levels of MAP2 and the activation of PARP protein markedly decreased in both Aβ (1-42) and Aβ (1-42) +TQ groups compared to the sham control groups Pearson's correlation test showed a positive relation between IL-1β and DCX in the Aβ (1-42) group. DISCUSSION: Our data suggested that TQ-related functional improvement might result from the increasing level of neurogenesis and ameliorating the level of IFN-γ in the Aβ (1-42) infused rat model of AD.

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“…Finally, the potential of flavonoids as ChE inhibitors was explored in recent literature reports to design hybrid compounds summing up the molecular motifs from isoflavones with the alkoxypiperidine motif, generating compounds with good activity profile on both H 3 R and AChE (Bajda et al., 2020; Łażewska et al., 2020; Wang et al., 2019). These compounds were identified in virtual screening campaigns, which were then synthesized and evaluated.…”

Section: Hybrid H3r/ache Ligandsmentioning

confidence: 99%

Histamine H₃ receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

2021

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The role of histamine and acetylcholine in cognitive functions suggests that compounds able to increase both histaminergic and cholinergic neurotransmissions in the brain should be considered as promising therapeutic options. For this purpose, dual inhibitors of histamine H 3 receptors (H 3 R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H 3 R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H 3 R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H 3 R antagonist pharmacophore with known anticholinesterase molecules were also reported. These reports strongly suggest that key modifications in the lipophilic region (including a second basic group) seem to be a strategy to reach novel compounds, allied with longer linker groups to a basic region. Some compounds have already demonstrated efficacy in memory models, although the pharmacokinetic and toxicity profile should be considered when designing further compounds. In conclusion, the key features to be considered when designing novel H 3 R/ChEs inhibitors with improved pharmacological profile were herein summarized.

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Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease

Cited by 29 publications

References 33 publications

Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Thymoquinone (TQ) demonstrates its neuroprotective effect via an anti-inflammatory action on the Aβ_(1–42)-infused rat model of Alzheimer's disease

Histamine H₃ receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

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Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease

Cited by 29 publications

References 33 publications

Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Thymoquinone (TQ) demonstrates its neuroprotective effect via an anti-inflammatory action on the Aβ(1–42)-infused rat model of Alzheimer's disease

Histamine H3 receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

Contact Info

Product

Resources

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Thymoquinone (TQ) demonstrates its neuroprotective effect via an anti-inflammatory action on the Aβ_(1–42)-infused rat model of Alzheimer's disease

Histamine H₃ receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands