Challenges and hopes for Alzheimer’s disease

Drug Discovery Today, Journal Year: 2022, Volume and Issue: 27(4), P. 1027 - 1043

Published: Feb. 1, 2022

Language: Английский

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Continuous-Flow Ritter Reaction for Sustainable Amide Synthesis Using a Recyclable m-Phenolsulfonic Acid-Formaldehyde Resin Catalyst

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 12, 2025

Herein, a rapid and efficient continuous-flow synthesis of amides is described. The Ritter reaction, catalyzed by reusable solid acid catalyst composed m-phenolsulfonic acid-formaldehyde resin (PAFR II), was used to convert nitriles alcohols in up 90% yield. system facilitates short reaction times maintains activity for several weeks. This method scalable, environmentally sustainable, enables recycling.

Language: Английский

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Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(3), P. 654 - 672

Published: Feb. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Language: Английский

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GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(16), P. 9098 - 9098

Published: Aug. 23, 2021

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial neurodegeneration context, deregulation of all three PKs has linked CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s (PD), frontotemporal lobar degeneration (FTLD), several neuromuscular disorders. The multifactorial nature these diseases, along failure many advanced clinical trials, lengthy approval process novel drug strongly limited discovery. However, near-decade from 2010 2020, computer-assisted design strategies combined synthetic efforts develop potent selective inhibitors disease-modifying agents. In this review, we described both structural functional aspects involvement crosstalk pathological signaling pathways. Moreover, outlined attractive medicinal chemistry approaches multi-target applied overcome some limitations known discover improved modulators suitable blood–brain barrier (BBB) permeability drug-like properties.

Language: Английский

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Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer's disease

European Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 222, P. 113554 - 113554

Published: May 30, 2021

Language: Английский

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The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2790 - 2790

Published: Oct. 18, 2021

Alzheimer’s disease (AD) is one of the most prominent neurodegenerative diseases, which impairs cognitive function in afflicted individuals. AD results gradual decay neuronal as a consequence diverse degenerating events. Several neuroimmune players (such cytokines and growth factors that are key maintaining CNS homeostasis) turn aberrant during crosstalk between innate adaptive immunities. This aberrance underlies neuroinflammation drives cells toward apoptotic decline. Neuroinflammation involves microglial activation has been shown to exacerbate AD. review attempted elucidate role cytokines, factors, associated mechanisms implicated course AD, especially with neuroinflammation. We also evaluated propensities specific mechanism(s) impacting neuron upon decline further shed light on availability accessibility across blood-brain barrier choroid plexus pathophysiology. The pathogenic protective roles macrophage migration inhibitory neurotrophic hematopoietic-related TAU phosphorylation, advanced glycation end products, complement system, glial neuropsychiatric pathology were discussed. Taken together, emerging these emphasize importance building novel strategies for an effective therapeutic/neuropsychiatric management clinics.

Language: Английский

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Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(5), P. 545 - 545

Published: April 28, 2022

Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis publications in period 1990-2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) number boomed by 2011 continued ascending 2020; (ii) linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores privileged structures; (iii) significant vivo studies, mainly using scopolamine-induced amnesia mouse model, been performed, especially since 2017; (iv) China, Italy Spain countries with largest total this topic, whereas Portugal, whose scientific communities topic has generated greatest interest; (v) acetylcholinesterase, β-amyloid aggregation, oxidative stress, butyrylcholinesterase, biometal chelation binary combinations thereof most commonly pursued, while other key targets, such as tau glycogen synthase kinase-3β, NMDA receptors, more than 70 targets only marginally considered. These results allow us to spot new opportunities innovative target expand diversify repertoire multitarget drug candidates increase likelihood finding effective therapies for devastating disease.

Language: Английский

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GSK-3β and its Inhibitors in Alzheimer's Disease: A Recent Update

Mini-Reviews in Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 22(22), P. 2881 - 2895

Published: April 22, 2022

Abstract: Alzheimer’s disease (AD) is an emerging major health and socioeconomic burden worldwide. It characterized by neuronal loss, memory loss cognitive impairment in the aging population. Despite several scientific advancements over past five decades, underlying molecular mechanism of progression yet unknown. Glycogen synthase kinase-3β (GSK-3β) has huge implications on brain function, causing pathologies, damage performance AD. one key players signaling pathways for normal functioning a critical link between amyloid-beta (Aβ) tau neurofibrillary tangles (NFTs). GSK-3β activation driven phosphorylation tau(τ) protein which results disruption synaptic activities formation plaques. Although accumulation Aβ plaques intracellular hyperphosphorylated been well established as neuropathological hallmarks disease, not unraveled. This review focuses role mechanisms participating manifestation The also suggests that inhibitors can be used potential therapeutic targets amelioration

Language: Английский

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Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease

Journal of Ethnopharmacology, Journal Year: 2022, Volume and Issue: 290, P. 115107 - 115107

Published: Feb. 14, 2022

Language: Английский

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Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases

Current Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 29(27), P. 4631 - 4697

Published: Feb. 16, 2022

GSK-3β activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer's disease is the most studied neurodegenerative disease, but seems be involved in almost all diseases, including Parkinson's amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's autoimmune multiple sclerosis.This review aims help researchers both working on this research topic or not have a comprehensive overview of context neurodegeneration.Literature searched using PubMed SciFinder databases by inserting specific keywords. A total more than 500 articles discussed.First all, structure regulation kinase were briefly discussed, then, implications diseases illustrated with figures, conclude important multitarget inhibitors. The IC50 values at target reported for discussed compounds.GSK-3β several signaling pathways neurons, glial cells immune cells. fine interconnection these are base rationale use GSK-β inhibitors Some compounds now under clinical trials. Despite this, compounds' pharmacodynamic ADME/Tox profiles often fully characterized which deleterious such complex system.

Language: Английский

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