Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer’s disease

Yang, Ziyi; Song, Qing; Cao, Zhongcheng; Yu, Guangjun; Liu, Zhuoling; Tan, Zhenghuai; Deng, Yong

doi:10.1016/j.bmc.2020.115374

Cited by 28 publications

(40 citation statements)

References 59 publications

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“…Interesting biological activities were also presented by flurbiprofen-clioquinol hybrids (68). Flurbiprofen is a known potent nonsteroidal anti-inflammatory drug, which also inhibits platelet aggregation and Aβ aggregation and reduces tau phosphorylation.…”

Section: Multifunctional Agents Focusing On Various Disease-modifying and Symptomatic Therapiesmentioning

confidence: 99%

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 Agents Focusing On Various Disease-modifying and Symptomatic Therapiesmentioning

confidence: 99%

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

Pasieka

Panek

Malawska

2020

Alzheimer’s Disease: Drug Discovery

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“…Individuals suffering from this neurodegenerative disorder, on the other hand, require constant human and medical care, which create a heavy socio-economic burden on the health care system [ 2 ]. Continued research on AD has revealed that low levels of acetylcholine, formation of β-amyloid (Aβ) deposits, oxidative stress, metal imbalance, inflammation, and immune suppression are involved in the pathogenesis and progression of AD [ 3 , 4 ]. The brains of AD patients generally show abnormal accumulation of β-amyloid (Aβ) plaques and the deposition of neurofibrillary tangles associated with oxidative damage [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…The most common therapeutic approach to counteract the effect of this multifactorial disease with interrelated factors is to raise the concentration of acetylcholine (ACh) through the inhibition of activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are responsible for the hydrolysis of ACh in the synaptic clefts. However, cholinesterase inhibitors only partly compensate the lost cognitive functions and have proven to be insufficient to slow down or to stop the neurodegenerative process itself [ 3 , 4 ]. It is envisioned that the treatment of AD would benefit from the use of multipotent drugs that target at least two or more key pathophysiological processes linked to AD, such as cholinesterases (AChE and/or BChE) and β-secretase activities as well oxidative stress [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and β-Secretase Inhibitors with Antioxidant Properties

Mphahlele

Agbo

et al. 2021

Antioxidants

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The 5-(styryl)anthranilamides were transformed into the corresponding 5-styryl-2-(p-tolylsulfonamido)benzamide derivatives. These 5-styrylbenzamide derivatives were evaluated through enzymatic assays in vitro for their capability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) activities as well as for antioxidant potential. An in vitro cell-based antioxidant activity assay involving lipopolysaccharides (LPS)-induced reactive oxygen species (ROS) production revealed that compounds 2a and 3b have the capability of scavenging free radicals. The potential of the most active compound, 5-styrylbenzamide (2a), to bind copper (II) or zinc (II) ions has also been evaluated spectrophotometrically. Kinetic studies of the most active derivatives from each series against the AChE, BChE, and β-secretase activities have been performed. The experimental results are complemented with molecular docking studies into the active sites of these enzymes to predict the hypothetical protein–ligand binding modes. Their drug likeness properties have also been predicted.

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“…Peptide aggregates lead to the death of affected hippocampal neurons [ 6 ]. Aβ plaques contribute to neuronal loss and ultimate failure of cognitive function [ 7 ]. The interaction of Aβ peptides with ions of copper, zinc, iron, aluminium, manganese, or mercury may contribute to neuronal damage [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Peptide aggregates lead to the death of affected hippocampal neurons [6]. Aβ plaques contribute to neuronal loss and ultimate failure of cognitive function [7].…”

Section: Introductionmentioning

confidence: 99%

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

2020

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Aluminium (Al) is clearly neurotoxic and considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer’s disease (AD). Nevertheless, the link between AD pathology and Al is still open to debate. Therefore, we investigated here the interaction of aluminium ions with two Aβ peptide fragments and their analogues. First, we synthesised by the Fmoc/tBu solid-phase peptide synthesis (SPPS) strategy using an automated peptide synthesiser two new peptides starting from the Aβ(1–16) native peptide fragment. For this purpose, the three histidine residues (H6, H13, and H14) of the Aβ(1–16) peptide were replaced by three alanine and three serine residues to form the modified peptides Aβ(1–16)A36,13,14 and Aβ(1–16)S36,13,14 (primary structures: H-1DAEFRADSGYEVAAQK16-NH2 and H-1DAEFRSDSGYEVSSQK16-NH2). In addition, the Aβ(9–16) peptide fragment (H-9GYEVHHQK16-NH2) and its glycine analogues, namely Aβ(9–16)G110, (H-9GGEVHHQK16-NH2), Aβ(9–16)G213,14 (H-9GYEVGGQK16-NH2), and Aβ(9–16)G310,13,14 (H-9GGEVGGQK16-NH2), were manually synthesised in order to study Al binding to more specific amino acid residues. Both the peptides and the corresponding complexes with aluminium were comparatively investigated by mass spectrometry (MS), circular dichroism spectroscopy (CD), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). Al–peptide molecular ions and Al-fragment ions were unambiguously identified in the MS and MS/MS spectra. AFM images showed dramatic changes in the film morphology of peptides upon Al binding. Our findings from the investigation of N-terminal 1-16 and even 9-16 normal and modified sequences of Aβ peptides suggest that they have the capability to be involved in aluminium ion binding associated with AD.

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Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer’s disease

Cited by 28 publications

References 59 publications

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

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

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and β-Secretase Inhibitors with Antioxidant Properties

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

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