Highly efficient, catalyst-free, one-pot sequential four-component synthesis of novel spiroindolinone-pyrazole scaffolds as anti-Alzheimer agents: <i>in silico</i> study and biological screening

Pourtaher, Hormoz; Mohammadi, Yasaman; Hasaninejad, Alireza; Iraji, Aida

doi:10.1039/d3md00255a

Cited by 3 publications

(2 citation statements)

References 66 publications

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“…The X-ray structures of AChE (PDB code: 4EY7) and BChE (PDB code: 4BDS) were prepared with the Protein Preparation Wizard interface. The molecular docking was performed according to the previpusly reported protocol 46 , 47 .…”

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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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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“…The primary site is situated at the base of a deep and narrow 20 Å gorge, encompassing the AChE catalytic triad and an anionic subsite called the catalytic active site (CAS). Additionally, there exists the peripheral anionic site (PAS) located near the entrance of the gorge [ 6 ]. The PAS plays a pivotal role, as it is thought to facilitate the aggregation process of amyloid-beta (Aβ), contributing to the intricate molecular mechanisms associated with AD [ 7 ].…”

Section: Introductionmentioning

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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Current pharmacophore based approaches for the development of new anti-Alzheimer’s agents

Sharma,

Yadav

et al. 2024

Bioorganic & Medicinal Chemistry

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Highly efficient, catalyst-free, one-pot sequential four-component synthesis of novel spiroindolinone-pyrazole scaffolds as anti-Alzheimer agents: in silico study and biological screening

Abstract: Alzheimer's disease is a neurodegenerative disorder that impacts memory, thinking, and behavior, and currently, there is no effective cure available for its treatment.

Cited by 3 publications

References 66 publications

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

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

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

Current pharmacophore based approaches for the development of new anti-Alzheimer’s agents

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