Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer’s Disease Therapy

Teponnou, Gerard A. K.; Joubert, Jacques; Malan, Sarel F.

doi:10.2174/1874104501711010024

Cited by 25 publications

(11 citation statements)

References 43 publications

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“…Trolox is a watersoluble vitamin E analog which due to its high capacity to capture ROS is used as a standard for the evaluation of the antioxidant capacity of other molecules [45]. Through its capacity to quench and react with single oxygen and neutralize free radical species, which indeed surpasses that of vitamin E [90,91], Trolox has been reported to prevent neurotoxicity induced by Aβ and hydrogen peroxide [92,93].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

2020

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Background: Mounting evidence points to a crucial role of amyloid-β (Aβ) in the pathophysiology of Alzheimer's disease (AD), a disorder in which brain glucose hypometabolism, downregulation of central elements of phosphorylation pathways, reduced ATP levels, and enhanced oxidative damage coexist, and sometimes precede, synaptic alterations and clinical manifestations. Since the brain has limited energy storage capacity, mitochondria play essential roles in maintaining the high levels of energy demand, but, as major consumers of oxygen, these organelles are also the most important generators of reactive oxygen species (ROS). Thus, it is not surprising that mitochondrial dysfunction is tightly linked to synaptic loss and AD pathophysiology. In spite of their relevance, the mechanistic links among ROS homeostasis, metabolic alterations, and cell bioenergetics, particularly in relation to Aβ, still remain elusive. Methods: We have used classic biochemical and immunocytochemical approaches together with the evaluation of real-time changes in global energy metabolism in a Seahorse Metabolic Analyzer to provide insights into the detrimental role of oligAβ in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.Results: Our findings indicate that oligomeric Aβ induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated Aβ-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of Aβ-challenged neurons with a set of small molecules of known antioxidant and cytoprotective activity prevented the metabolic/bioenergetic changes induced by the peptide, fully restoring mitochondrial function while inducing an antioxidant response that counterbalanced the ROS production. Search for a mechanistic link among the protective small molecules tested identified the transcription factor Nrf2compromised by age and downregulated in AD and transgenic models-as their main target and the PI3K/GSK-3 axis as the central pathway through which the compounds elicit their Aβ protective action. Conclusions:Our study provides insights into the complex molecular mechanisms triggered by oligAβ which profoundly affect mitochondrial performance and argues for the inclusion of small molecules targeting the PI3K/ GSK-3 axis and Nrf2-mediated pathways as part of the current or future combinatorial therapies.

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Section: Discussionmentioning

confidence: 99%

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

2020

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“…DPPH + and trolox were purchased from Sigma-Aldrich ® . The following method was employed, as previously described 48 , to determine the antioxidant activity of the test compounds. Each well of a 96 well plate, contained the following: 180 µL of 0.12 mM DPPH + dissolved in methanol and 20 µL of either test compound, control (trolox) or blank (DMSO).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

Zondagh

Malan

Joubert

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dualsite inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC 50 : 1.2-4.6 mM) with limited butyrylcholinesterase inhibitory activity (IC 50 's >160 mM), indicating excellent selectivity towards AChE (SI: 46->278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood-brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents.

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“…Based on the topology of the active site of AChE and BChE, Teponnou et al . [179] designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The compounds with trolox moiety ( 21a-d ) exhibited AChE/BChE inhibition and free radical scavenging activities with IC 50 values of 17.37-2200 nM, 3.16-128.82 nM and 11.48-49.23 µM, respectively.…”

Section: New Multifunctional Analogues and Hybrids Of Tacrinementioning

confidence: 99%

Therapeutic Potential of Multifunctional Tacrine Analogues

Przybyłowska

Kowalski

Dzierzbicka

et al. 2019

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Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as model inhibitor of cholinesterases in the therapy of Alzheimer's disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer's disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist a new paradigm to treat Alzheimer's disease. We have also reported potential of these analogues in the treatment of Alzheimer's diseases in various experimental systems.

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Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer’s Disease Therapy

Cited by 25 publications

References 43 publications

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

Therapeutic Potential of Multifunctional Tacrine Analogues

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