Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer’s Disease Therapy

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(4), P. 745 - 771

Published: Feb. 8, 2024

An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) β-secretase (hBACE-1) that exhibit moderate good inhibitory effects. Compounds AV-1, AV-2, AV-3 from demonstrated balanced significant inhibition these targets. These compounds also displayed excellent blood–brain barrier permeability via PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) acetylcholinesterase-peripheral anionic site (AChE-PAS) was found be non-neurotoxic at maximum tested concentration (80 μM) differentiated SH-SY5Y cell lines. prevented AChE- self-induced Aβ aggregation thioflavin T Additionally, compound ameliorated scopolamine Aβ-induced cognitive impairments vivo behavioral Y-maze Morris water maze studies, respectively. The ex biochemical analysis further revealed hippocampal AChE antioxidant potential AV-2. Western blot immunohistochemical (IHC) brain reduced Aβ, BACE-1, APP/Aβ, Tau molecular protein expressions levels. pharmacokinetic oral absorption with bioavailability. silico modeling studies lead moreover reasonable binding profile BACE-1 enzymes stable ligand–protein complexes throughout 100 ns run. can regarded candidate could explored more for AD therapy.

Language: Английский

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Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer’s Disease Therapy

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(11), P. 2217 - 2242

Published: May 22, 2023

Our present work demonstrates the successful design and synthesis of a new class compounds based upon multitargeted directed ligand approach to discover agents for use in Alzheimer's disease (AD). All were tested their vitro inhibitory potential against human acetylcholinesterase (hAChE), butylcholinesterase (hBChE), β-secretase-1 (hBACE-1), amyloid β (Aβ) aggregation. Compounds 5d 5f have shown hAChE hBACE-1 inhibition comparable donepezil, while hBChE was rivastigmine. also demonstrated significant reduction formation Aβ aggregates through thioflavin T assay confocal, atomic force, scanning electron microscopy studies significantly displaced total propidium iodide, that is, 54 51% at 50 μM concentrations, respectively. devoid neurotoxic liabilities RA/BDNF (RA = retinoic acid; BDNF brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines 10–80 concentrations. In both scopolamine- Aβ-induced mouse models AD, restoration learning memory behaviors. A series ex vivo hippocampal cortex brain homogenates showed elicit decreases AChE, malondialdehyde, nitric oxide levels, an increase glutathione level, reduced levels pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) interleukin-6 (IL-6) mRNA. The histopathological examination mice revealed normal neuronal appearance regions brain. Western blot analysis same tissue indicated Aβ, precursor protein (APP)/Aβ, BACE-1, tau which non-significant compared sham group. immunohistochemical lower expression BACE-1 donepezil-treated represent lead candidates developing AD therapeutics.

Language: Английский

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Carbamate as a potential anti‐Alzheimer's pharmacophore: A review

Drug Development Research, Journal Year: 2023, Volume and Issue: 84(8), P. 1624 - 1651

Published: Sept. 11, 2023

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms AD pathogenesis are very complex still not fully explored. Cholinergic neuronal loss, accumulation amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, mitochondrial dysfunction major hallmarks AD. current treatment options for acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects progression. So, there an urgent need novel drug development that only addresses basic but also shows neuroprotective property. Various research groups across globe working on multifunctional agents amelioration using different core scaffolds their design, carbamate among them. Rivastigmine was first investigated management. fragment, scaffold act as potential inhibitor acetylcholinesterase. In this review, we summarize last 10 years conducted modification with substituents primarily target ChE inhibition, reduce modulate Aβ aggregation.

Language: Английский

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Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer’s disease

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 139, P. 106749 - 106749

Published: July 23, 2023

Language: Английский

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Advances of metallodrug-amyloid β aggregation inhibitors for therapeutic intervention in neurodegenerative diseases: Evaluation of their mechanistic insights and neurotoxicity

Coordination Chemistry Reviews, Journal Year: 2023, Volume and Issue: 501, P. 215580 - 215580

Published: Dec. 1, 2023

Language: Английский

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Molecular Targets of Valeric Acid: A Bioactive Natural Product for Endocrine, Metabolic, and Immunological Disorders

Endocrine Metabolic & Immune Disorders - Drug Targets, Journal Year: 2024, Volume and Issue: 24(13), P. 1506 - 1517

Published: Feb. 20, 2024

Backgrounds: Postbiotics produced by gut microbiota have exhibited diverse pharmacological activities. Valeric acid, a postbiotic material and some plant species like valerian, has been explored to Methods: This narrative review aims summarise the beneficial role of valeric acid for different health conditions along with its underlying mechanism. In order get ample scientific evidence, various databases Science Direct, PubMed, Scopus, Google Scholar were exhaustively collect relevant information. Collected data arranged analyzed reach meaningful conclusion regarding bioactivity profiling mechanism, future prospects. Results: belongs short-chain fatty acids (SCFAs) compounds acetate, propionate, butyrate, pentanoic (valeric) hexanoic (caproic) acid. identified as one potent histone deacetylase (HDAC) inhibitors. preclinical in -vitro in-vivo studies, found anti-cancer, anti-diabetic, antihypertensive, anti-inflammatory, immunomodulatory activity affects molecular pathways diseases Alzheimer’s, Parkinson’s, epilepsy. Conclusion: These findings highlight potential novel therapeutic agent endocrine, metabolic immunity-related conditions, it must be tested under clinical develop promising drug.

Language: Английский

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Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer’s Disease

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(7), P. 1388 - 1414

Published: March 25, 2024

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks disease. In our ongoing efforts develop naturally inspired novel multifunctional molecules AD, systematic SAR studies on EJMC-4e were caried out improve its properties. rigorous medicinal led development 12o, displayed a 15-fold enhancement antioxidant properties 2-fold activity against AChE BChE over EJMC-4e. Molecular docking dynamics revealed binding sites stability complex 12o BChE. PAMPA-BBB assay clearly demonstrated that easily cross blood–brain barrier. Interestingly, also expresses promising chelation activity, while was found be devoid this property. Further, inhibited metal-induced or self Aβ1–42 aggregation. Observing neuroprotection ability H2O2-induced stress PC-12 cell line noteworthy. Furthermore, NLRP3 inflammasome activation attenuated mitochondrial-induced ROS MMP damage caused by LPS ATP HMC-3 cells. addition, able effectively reduce mitochondrial cellular Drosophila model. Finally, could reverse memory impairment scopolamine-induced mice model, as evident through vivo ex studies. These findings suggest compound may act candidate further improvement management AD.

Language: Английский

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Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 271, P. 116450 - 116450

Published: April 27, 2024

Language: Английский

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Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 104(4)

Published: Oct. 1, 2024

ABSTRACT Alzheimer's disease (AD) is a chronic progressive, age‐related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It one major health threat 21st century, which affects around 60% population over age 60 years. The problem this even more because existing pharmacotherapies only provide symptomatic relief without addressing basic factors disease. extracellular deposition amyloid β (Aβ) to form senile plaques, intracellular hyperphosphorylation tau neurofibrillary tangles (NFTs). Due complex pathophysiology disease, various hypotheses have been proposed, including cholinergic, Aβ, tau, oxidative stress, metal–ion hypothesis. Among these, cholinergic Aβ are primary targets for AD. Therefore, continuous advances made in developing potential cholinesterase inhibitors N ‐methyl‐D‐aspartate (NMDA) receptor antagonists delay progression restore neurotransmission. In review article, we tried comprehensively summarize recent advancement NMDA antagonist (memantine) their hybrid analogs as disease‐modifying agents treatment Furthermore, also depicted design, rationale, SAR analysis memantine‐based hybrids used last decade

Language: Английский

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Tryptamine: A privileged scaffold for the management of Alzheimer's disease

Drug Development Research, Journal Year: 2023, Volume and Issue: 84(8), P. 1578 - 1594

Published: Sept. 7, 2023

Abstract Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative associated with aging. It characterized by the progressive loss of memory other cognitive functions. Although exact etiology AD not well explored, several factors, such as deposition amyloid‐β (Aβ) plaques, hyperphosphorylation tau protein, presence low levels acetylcholine, generation oxidative stress, are key mediators in progression AD. Currently, clinical treatment options for limited based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, galantamine), N ‐methyl‐ d ‐aspartic acid receptor antagonists memantine), recently approved Aβ modulator aducanumab). Tryptamine (2‐(1 H ‐indol‐3‐yl)ethan‐1‐amine) small molecule that contains an indole nucleus ethylamine side chain. also active metabolite tryptophan. possesses wide range biological activities related to disorders, ChE inhibition, aggregation antioxidant effects, monoamine‐oxidase neuroprotection. Several tryptamine‐based hybrid analogs currently being investigated multifunctional agents development novel hybrids treatment. Thus, this review article aims provide in‐depth insights into research progress strategies designing used therapy.

Language: Английский

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