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

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(4), С. 745 - 771

Опубликована: Фев. 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.

Язык: Английский

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Crosstalk Between the NLRP3 Inflammasome/ASC Speck and Amyloid Protein Aggregates Drives Disease Progression in Alzheimer’s and Parkinson’s Disease

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Фев. 3, 2022

Two key pathological hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s (PD), are the accumulation misfolded protein aggregates chronic progressive neuroinflammation that they trigger. Numerous original research reviews have provided a comprehensive understanding how aggregated proteins (amyloid β, tau, α-synuclein) contribute to disease, driving sterile inflammation, in part, through aggregation multi-protein inflammasome complexes ASC speck [composed NOD-, LRR-, pyrin domain-containing 3 (NLRP3), Apoptosis-associated speck-like containing C-terminal caspase activation recruitment domain (ASC), inflammatory caspase-1] involved innate immunity. Here, we provide unique perspective on crosstalk between aggregation-prone AD/PD complex/ASC fuels feed-forward exacerbation each other, neurodegeneration. Failed turnover (both related speck) by degradation pathways, prionoid propagation inflammation speck, cross-seeding pro-aggregatory cleavage caspase-1 some mechanisms exacerbate progression. We also review studies this causal framework highlight serves as platform for spreading drives AD PD.

Язык: Английский

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From 1901 to 2022, how far are we from truly understanding the pathogenesis of age-related dementia?

GeroScience, Год журнала: 2022, Номер 44(3), С. 1879 - 1883

Опубликована: Май 19, 2022

Язык: Английский

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Small-molecule theranostics in Alzheimer's disease

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 255, С. 115382 - 115382

Опубликована: Апрель 22, 2023

Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed countries, due to rising life expectancy and, moreover, represents a considerable economic burden worldwide. All efforts at discovery new diagnostic and therapeutic tools last decades have invariably met with failure, making AD an incurable illness underscoring need approaches. In recent years, theranostic agents emerged as interesting strategy. They are molecules able simultaneously provide information deliver activity, allowing assessment molecule organism response pharmacokinetics. This makes these compounds promising streamlining research on drugs their application personalized medicine. We review here field small-molecule development novel resources against AD, highlighting positive significant impact that theranostics can be expected near future clinical practice.

Язык: Английский

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Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Март 10, 2023

The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson’s disease, Amyotrophic Lateral Sclerosis, Alzheimer’s along with protein misfolding. aberrantly folded proteins known to link impaired pathways, further contributing disease pathogenesis. Despite their central significance, implications disruption on other organelles cellular processes remain insufficiently explored. Here, we have reviewed dysfunction physiology, under degenerating conditions. misfolded impact quality control mechanisms mitochondria, such as fission, fusion, mitophagy, proteasomal clearance, detriment neuron. adversely affected functional roles, oxidative phosphorylation, calcium homeostasis, biomolecule synthesis well its axes contacts endoplasmic reticulum lysosomes also discussed. Mitochondria sense respond multiple cytotoxic stress make cell adapt survive, though chronic leads death. can be candidates for biomarkers therapeutic targets. Investigation internetworking between mitochondria neurodegeneration enhance our holistic understanding conditions help designing more targeted therapies.

Язык: Английский

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