Development of novel rivastigmine derivatives as selective BuChE inhibitors for the treatment of AD

Bioorganic Chemistry, Год журнала: 2025, Номер 157, С. 108245 - 108245

Опубликована: Фев. 6, 2025

Язык: Английский

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Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Biomolecules, Год журнала: 2022, Номер 12(11), С. 1676 - 1676

Опубликована: Ноя. 11, 2022

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, synaptic nonsynaptic plasticity the lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury synapses neurons accumulation extracellular amyloid plaques intracellular neurofibrillary tangles are considered main morphological neuropathological features AD. Age, genetic epigenetic factors, environmental stressors, lifestyle contribute risk AD onset progression. These factors associated with structural functional changes brain, leading cognitive decline. Biomarkers reflect cause specific function, especially pathways neurotransmission, neuroinflammation, bioenergetics, apoptosis, oxidative nitrosative stress. Even initial stages, is Aβ neurotoxicity, mitochondrial dysfunction, tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that primary neurotoxicity oligomers oligomers, their mutual synergy. For development new efficient drugs, targeting elimination potentiation effects, unwanted protein interactions biomarkers (mainly dysfunction) early stage seems promising.

Язык: Английский

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Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

ACS Omega, Год журнала: 2022, Номер 7(51), С. 47504 - 47517

Опубликована: Дек. 13, 2022

A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various models are available several diseases, clinical Alzheimer's (AD) remain underdeveloped inaccurate. The pathophysiology of AD mainly includes presence amyloid plaques neurofibrillary tangles (NFT). Furthermore, neuroinflammation free radical generation also contribute AD. Currently, there wide gap in scientific approaches preventing progression. Most drugs limited symptomatic relief improve deteriorating cognitive functions. To mimic pathogenesis AD, animal like 3XTg-AD 5XFAD primarily used mice therapeutics. Animal include intracerebroventricular-streptozotocin (ICV-STZ), beta-induced, colchicine-induced, etc., focusing on parameters such as decline dementia. Unfortunately, translational rate potential candidates trials poor due limitations imitating pathology models. Therefore, possess modeling. This paper presents an outline that critically assesses applicability current modeling Also, we attempted provide key suggestions best-fit evaluate therapies, which might therapy translation from studies patients with

Язык: Английский

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Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 261, С. 115817 - 115817

Опубликована: Сен. 14, 2023

Язык: Английский

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New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5383 - 5383

Опубликована: Март 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Язык: Английский

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Design, synthesis and anticholinesterase activity of coumarin-1,3,5-triazine derivatives

Journal of Molecular Structure, Год журнала: 2025, Номер unknown, С. 142439 - 142439

Опубликована: Апрель 1, 2025

Язык: Английский

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Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)

Опубликована: Янв. 23, 2023

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated AChE/BuChE inhibition anti-inflammatory property. in vitro activities showed that compound 3f a reversible dual eeAChE/eqBuChE inhibitor with IC50 values 1.3 µM 0.81 µM, respectively. Moreover, displayed good property decreasing the production IL-6, IL-1β NO. In addition, presented significant neuroprotective effect on Aβ25-35-induced PC12 cell injury. Furthermore, stabilities artificial gastrointestinal fluids, liver microsomes plasma. could improve AlCl3-induced zebrafish AD model increasing level ACh. Therefore, promising multifunctional agent treatment AD.

Язык: Английский

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Development of the “hidden” multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 251, С. 115253 - 115253

Опубликована: Март 10, 2023

Язык: Английский

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Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases

Medicinal Research Reviews, Год журнала: 2024, Номер 44(4), С. 1404 - 1445

Опубликована: Янв. 27, 2024

Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate principal roles signaling systems cyclic adenosine guanosine 3',5'-monophosphates (cAMP cGMP) in functions, summarize expression/activity changes associated enzymes ND patients, including cyclases, protein kinases, phosphodiesterases (PDEs). As sole hydrolyzing cAMP cGMP, PDEs logical targets for modification neurodegeneration. We focus on PDE inhibitors their potentials disease-modifying therapeutics treatment Alzheimer's disease, Parkinson's Huntington's disease. For overlapped but distinct contributions cGMP NDs, we hypothesize that dual inhibitors, which simultaneously regulate both pathways, may have complementary synergistic effects modifying neurodegeneration thus represent a new direction discovery drugs.

Язык: Английский

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Identification of DprE1 inhibitors for tuberculosis through integrated in-silico approaches

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 17, 2024

Abstract Decaprenylphosphoryl-β-D-ribose-2′-epimerase (DprE1), a crucial enzyme in the process of arabinogalactan and lipoarabinomannan biosynthesis, has become target choice for anti-TB drug discovery recent past. The current study aims to find potential DprE1 inhibitors through in-silico approaches. Here, we built pharmacophore 3D-QSAR model using reported 40 azaindole derivatives inhibitors. best hypothesis (ADRRR_1) was employed virtual screening chEMBL database. To identify prospective hits, molecules with good phase scores (> 2.000) were further evaluated by molecular docking studies their ability bind (PDB: 4KW5). Based on binding affinities (< − 9.0 kcal/mole), hits subjected calculation free-binding energies (Prime/MM-GBSA), pharmacokinetic, druglikeness evaluations. top 10 retrieved from these results selected predict inhibitory activities via developed regression coefficient (R 2 ) value 0.9608 predictive (Q 0.7313. induced fit (IFD) prediction sensitivity also implemented. Molecular dynamics simulations (MDS) performed 5 hit 200 ns check stability DprE1. conformational throughout simulation, (chEMBL_SDF:357100) identified as against an accepted safety profile. MD accordance score, MM-GBSA value, predicted activity. molecule, (N-(3-((2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)phenyl)acrylamide) could serve lead novel inhibiting drug.

Язык: Английский

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