Targeting Free Radicals in Oxidative Stress-Related Human Diseases

Trends in Pharmacological Sciences, Год журнала: 2017, Номер 38(7), С. 592 - 607

Опубликована: Май 24, 2017

Язык: Английский

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Management of oxidative stress and other pathologies in Alzheimer’s disease

Archives of Toxicology, Год журнала: 2019, Номер 93(9), С. 2491 - 2513

Опубликована: Авг. 22, 2019

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by the formation, aggregation and accumulation of amyloid beta, perturbed metal (copper, iron zinc) homeostasis, metal-induced oxidative stress, neuroinflammation, aberrant activity acetylcholinesterase (AChE) other pathologies. The aim this review to discuss current therapies based on "combination-drugs-multitargets" strategy target multiple pathologies block progression pathogenesis AD. In addition cholinergic targets, significant effort focused targeting stress component disease. main focus research modifications existing drugs with specific biological activity. Tacrine was first AChE inhibitor be introduced into clinical practice has been frequently used for design multitarget-directed ligands. A number hybrid compounds containing tacrine structural moieties derived from natural sources such as flavonoids [quercetin, rutin, coumarin, gallamine, resveratrol, scutellarin, anisidine, hesperetin, (−)-epicatechin] molecules (melatonin, trolox) have also applied function Most these hybrids are potent inhibitors butyrylcholinesterase amyloid-beta aggregation. addition, antioxidant functionality, represented coumarins, melatonin reduces level via ROS-scavenging mechanisms, well chelation redox-active Cu Fe, thus suppressing formation ROS Fenton reaction. Various medicinal plants under investigation their ability ameliorate symptoms therapeutic potency huperzine B, ginseng, curcumin manifested predominantly inhibitory action toward AChE, or radical-scavenging redox metal-chelating activity, inhibition tau-protein hyperphosphorylation antiinflammatory Flavonoids not only antioxidants agents, but interact protein kinase lipid signaling pathways, others involving mitogen-activated kinase, NF-kappaB tyrosine kinase. Among most promising group substances potential against AD flavonoids, including myricetin, morin, quercetin, fisetin, kaempferol, apigenin glycitein, which shown, in vitro, possess antiamyloidogenic fibril-destabilization being able act chelators stress. terms use multifunctional hybrids, herbal AD, some remaining challenges establish ideal dose develop effective formulations preserve bioavailability determine stage when they should administered. If onset could delayed decade, victims would significantly reduced.

Язык: Английский

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A Perspective on Multi-target Drugs for Alzheimer’s Disease

Trends in Pharmacological Sciences, Год журнала: 2020, Номер 41(7), С. 434 - 445

Опубликована: Май 21, 2020

Язык: Английский

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Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer's disease

European Journal of Medicinal Chemistry, Год журнала: 2018, Номер 158, С. 463 - 477

Опубликована: Сен. 13, 2018

Язык: Английский

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Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease

Biomedicine & Pharmacotherapy, Год журнала: 2017, Номер 98, С. 297 - 307

Опубликована: Дек. 27, 2017

Язык: Английский

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Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease

European Journal of Medicinal Chemistry, Год журнала: 2019, Номер 168, С. 491 - 514

Опубликована: Фев. 27, 2019

Язык: Английский

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Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer’s Disease Drug Discovery

ACS Medicinal Chemistry Letters, Год журнала: 2018, Номер 9(3), С. 171 - 176

Опубликована: Фев. 9, 2018

Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) human acetylcholinesterase (hAChE), might represent breakthrough in quest for clinical efficacy. Thus, novel family GSK-3β/AChE dual-target inhibitors was designed synthesized. Among these hybrids, 2f showed most profile nanomolar inhibitor on both hAChE (IC50 = 6.5 nM) hGSK-3β kinase activity 66 nM). It also good inhibitory effect β-amyloid self-aggregation (inhibitory rate 46%) at 20 μM. Western blot analysis revealed that compound inhibited hyperphosphorylation tau protein mouse neuroblastoma N2a-Tau cells. In vivo studies confirmed significantly ameliorated cognitive disorders scopolamine-treated ICR mice less hepatotoxicity than tacrine. This study provides new leads assessment GSK-3β AChE pathway dual strategy treatment.

Язык: Английский

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Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(8), С. 4972 - 4990

Опубликована: Апрель 8, 2021

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack effective drugs as well basis development "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there need new that are not only but also accessible. With this motivation, we report first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied framework combination functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, microglial cell toxicity. Enzymatic studies disclosed potent selective AChE/BChE inhibitors (5, 6, 12), subnanomolar activities. X-ray crystal structure 5 complexed BChE allowed rationalizing observed activity (0.0352 nM). Investigation BV-2 cells revealed antineuroinflammatory neuroprotective activities 6 (already at 0.01 μM), confirming design rationale.

Язык: Английский

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Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery

International Journal of Biological Macromolecules, Год журнала: 2022, Номер 210, С. 172 - 181

Опубликована: Май 6, 2022

Язык: Английский

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Tacrine-Based Hybrids: Past, Present, and Future

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(2), С. 1717 - 1717

Опубликована: Янв. 15, 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder which characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks AD are oxidative stress, metal dyshomeostasis, inflammation, cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development anti-AD drugs, “one drug–multiple targets” strategy current interest. Tacrine (THA) was first clinically approved cholinesterase (ChE) inhibitor, withdrawn due to high hepatotoxicity. However, its potency in ChE inhibition, low molecular weight, simple structure make THA promising scaffold developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 2022, thus providing an overview strategies that have been used drug design approaches resulted significant cognitive improvements reduced

Язык: Английский

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