Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3β level targeting Alzheimer's disease

Noori, Milad; Dastyafteh, Navid; Safapoor, Sajedeh; Khalili Ghomi, Minoo; Tanideh, Romina; Zomorodian, Kamiar; Hamedifar, Haleh; Dara, Mahintaj; Zare, Shahrokh; Irajie, Cambyz; Javanshir, Shahrzad; Rastegar, Hossein; Panahi, Nikoo; Larijani, Bagher; Mahdavi, Mohammad; Hajimiri, Mir H.; Iraji, Aida

doi:10.1016/j.ijbiomac.2023.127392

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…The absorbance of each well was measured at 415 nm using a microplate reader. IC50 values were calculated with GraphPad Prism software, representing the mean of three independent experiments and expressed as mean ± SEM [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study

Nazarian,

Abedinifar,

Hamedifar

et al. 2024

BMC Chemistry

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In pursuit of developing novel cholinesterase (ChE) inhibitors through molecular hybridization theory, a novel series of isoindolin-1,3-dione-based acetohydrazides (compounds 8a–h) was designed, synthesized, and evaluated as possible acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In vitro results revealed IC50 values ranging from 0.11 ± 0.05 to 0.86 ± 0.02 µM against AChE and 5.7 ± 0.2 to 30.2 ± 2.8 µM against BChE. A kinetic study was conducted on the most potent compound, 8a, to ascertain its mode of inhibition, revealing its competitive mode against AChE. Furthermore, the binding interaction modes of the most active compound within the AChE active site was elucidated. Molecular dynamics simulations of compound 8a were performed to assess the stability of the 8a-AChE complex. In silico pharmacokinetic predictions for the most potent compounds indicated their potential as promising lead structure for the development of new anti-Alzheimer’s disease (anti-AD) agents.

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Section: Methodsmentioning

confidence: 99%

Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study

Nazarian,

Abedinifar,

Hamedifar

et al. 2024

BMC Chemistry

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“…Docked complexes of AChE and BChE complexed with 3m and apo enzymes were used for the MD simulation according to a previous study using the Schoringer package 48 , 49 .…”

Section: Methodsmentioning

confidence: 99%

Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents

Loori,

Pourtaher,

Mehranpour

et al. 2024

Sci Rep

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Alzheimer’s disease (AD), a severe neurodegenerative disorder, imposes socioeconomic burdens and necessitates innovative therapeutic strategies. Current therapeutic interventions are limited and underscore the need for novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes implicated in the pathogenesis of AD. In this study, we report a novel synthetic strategy for the generation of 2-aminopyridine derivatives via a two-component reaction converging aryl vinamidinium salts with 1,1-enediamines (EDAMs) in a dimethyl sulfoxide (DMSO) solvent system, catalyzed by triethylamine (Et3N). The protocol introduces a rapid, efficient, and scalable synthetic pathway, achieving good to excellent yields while maintaining simplistic workup procedures. Seventeen derivatives were synthesized and subsequently screened for their inhibitory activity against AChE and BChE. The most potent derivative, 3m, exhibited an IC50 value of 34.81 ± 3.71 µM against AChE and 20.66 ± 1.01 µM against BChE compared to positive control donepezil with an IC50 value of 0.079 ± 0.05 µM against AChE and 10.6 ± 2.1 µM against BChE. Also, detailed kinetic studies were undertaken to elucidate their modes of enzymatic inhibition of the most potent compounds against both AChE and BChE. The promising compound was then subjected to molecular docking and dynamics simulations, revealing significant binding affinities and favorable interaction profiles against AChE and BChE. The in silico ADMET assessments further determined the drug-like properties of 3m, suggesting it as a promising candidate for further pre-clinical development.

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“…The primary objective to replace phenyl with quinoline was to target the larger binding site of BChE. 67 It is noteworthy to observe the significant improvement toward BChE activity in the developed compound 10a−10e (Table 1). Given the importance of metals in AD progression, our next goal was to introduce metal chelator, Aβ modulator, and antioxidant enhancer fragment.…”

Section: Introductionmentioning

confidence: 99%

“…Given the well-tolerated behavior of quinoline toward AChE and BChE in EJMC-7b (IC 50 , (μM) AChE, 4.89 ± 0.37, and BChE, 14.32 ± 0.04), we next replaced the distal phenyl ring with different positions of quinoline ring to develop 10a – 10e . The primary objective to replace phenyl with quinoline was to target the larger binding site of BChE . It is noteworthy to observe the significant improvement toward BChE activity in the developed compound 10a – 10e (Table ).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Ferulic Acid-Piperazine Derivatives Targeting Pathological Hallmarks of Alzheimer’s Disease

Singh,

Kumar,

Panda

et al. 2024

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is the most prevalent cause of dementia and is characterized by low levels of acetyl and butyrylcholine, increased oxidative stress, inflammation, accumulation of metals, and aggregations of Aβ and tau proteins. Current treatments for AD provide only symptomatic relief without impacting the pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multitarget molecules for AD, through extensive medicinal chemistry efforts, we have developed 13a, harboring the key functional groups to provide not only symptomatic relief but also targeting oxidative stress, able to chelate iron, inhibiting NLRP3, and Aβ 1−42 aggregation in various AD models. 13a exhibited promising anticholinesterase activity against AChE (IC 50 = 0.59 ± 0.19 μM) and BChE (IC 50 = 5.02 ± 0.14 μM) with excellent antioxidant properties in DPPH assay (IC 50 = 5.88 ± 0.21 μM) over ferulic acid (56.49 ± 0.62 μM). The molecular docking and dynamic simulations further corroborated the enzyme inhibition studies and confirmed the stability of these complexes. Importantly, in the PAMPA-BBB assay, 13a turned out to be a promising molecule that can efficiently cross the blood−brain barrier. Notably, 13a also exhibited iron-chelating properties. Furthermore, 13a effectively inhibited self-and metal-induced Aβ 1−42 aggregation. It is worth mentioning that 13a demonstrated no symptom of cytotoxicity up to 30 μM concentration in PC-12 cells. Additionally, 13a inhibited the NLRP3 inflammasome and mitigated mitochondrial-induced reactive oxygen species and mitochondrial membrane potential damage triggered by LPS and ATP in HMC-3 cells. 13a could effectively reduce mitochondrial and cellular reactive oxygen species (ROS) in the Drosophila model of AD. Finally, 13a was found to be efficacious in reversing memory impairment in a scopolamine-induced AD mouse model in the in vivo studies. In ex vivo assessments, 13a notably modulates the levels of superoxide, catalase, and malondialdehyde along with AChE and BChE. These findings revealed that 13a holds promise as a potential candidate for further development in AD management.

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Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3β level targeting Alzheimer's disease

Cited by 6 publications

References 30 publications

Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study

Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study

Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents

Design, Synthesis, and Biological Evaluation of Ferulic Acid-Piperazine Derivatives Targeting Pathological Hallmarks of Alzheimer’s Disease

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