Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: Characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity

Bukhari, Syed Nasir Abbas; Jantan, Ibrahim; Masand, Vijay H.; Mahajan, Devidas T.; Sher, Muhammad; Naeem-ul-Hassan, Muhammad; Amjad, Muhammad Wahab

doi:10.1016/j.ejmech.2014.06.034

Cited by 50 publications

(45 citation statements)

References 36 publications

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“…In our recent studies, we reported the synthesis of 30 novel α, β‐unsaturated carbonyl‐based compounds. Among these compounds, the most potent AChE inhibitors were found to be N ‐methyl‐4‐piperidone and 4‐piperidone moieties, which had substitution at R 1 position in cyclohexanone ring …”

Section: Resultsmentioning

confidence: 99%

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

et al. 2016

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Neurodegeneration, a complex disease state, comprises several pathways that contribute to cell death. Conventional approach of targeting only one of these pathways has not been proven to be entirely successful and has demanded a hypothetical change as to how researchers design and develop new drugs. In this study, effects of a series of α, β-unsaturated carbonyl-based tetralone derivatives against Alzheimer's disease (AD) were investigated. Moreover, their activity toward amyloid β-induced cytotoxicity was also studied. Six compounds including 3f, 3o, 3u, 3ae, 3af, and 3ag were discovered to be most protective against Aβ-induced neuronal cell death in PC12 cells. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against MAO-B, AChE, and self-induced Aβ aggregation. The compound 3f exhibited best AChE (IC = 0.045 ± 0.02 μm) inhibitory potential in addition to potent inhibition of MAO-B (IC = 0.88 ± 0.12 μm). Furthermore, compound 3f disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 78.2 ± 4.8%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment.

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Section: Resultsmentioning

confidence: 99%

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

et al. 2016

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“…Thus, the hydrophobic surfaces of naked (chaperone‐free) partially folded proteins that are missing their proper folding need to be bound to chaperones to prevent the aggregation of proteins that make up complexes (Fig. ) .…”

Section: General Introduction To Protein Misfolding and Aggregation/amentioning

confidence: 99%

“…All amyloid fibrils have characteristic elongated fibrillar morphology with a ß‐sheet‐rich structure. The formation of well‐ordered fibrillar protein deposits is common to a large group of amyloid associated disorders such as AD, PD, prion diseases, HD, and familial amyloidosis .…”

Section: General Introduction To Protein Misfolding and Aggregation/amentioning

confidence: 99%

“…Stacking of aromatic residues plays a major role in the acceleration of assembly process, whereby provides an energetic contribution as well as directionality and orientation of amyloid fibril formation . Another well‐known characteristic of all amyloid fibrils is their interaction with specific heteroaromatic compounds retained planer structures, and can be regarded as functional dyes such as methylene blue and thioflavin T, which show definite optical behavior .…”

Section: General Introduction To Protein Misfolding and Aggregation/amentioning

confidence: 99%

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Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases

2016

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Protein misfolding and inclusion body formations are common events in neurodegenerative diseases characterized by deposition of misfolded proteins inside or outside of neurons, and are commonly referred to as "protein misfolding neurodegenerative diseases" (PMNDs). These phenotypically diverse but biochemically similar aggregates suggest a highly conserved molecular mechanism of pathogenesis. These challenges are magnified by presence of mutations that render individual proteins subject to misfolding and/or aggregation. Cell proteostasis network and molecular chaperoning are maintaining cell proteome to preserve the protein folding, refolding, oligomerization, or disaggregation, and play formidable tasks to maintain the health of organism in the face of developmental changes, environmental insults, and rigors of aging. Maintenance of cell proteome requires the orchestration of major pathways of the cellular proteostasis network (heat shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the endoplasmic reticulum). Proteostasis responses culminate in transcriptional and post-transcriptional programs that up-regulate the homeostatic mechanisms. Proteostasis is strongly influenced by the general properties of individual proteins for folding, misfolding, and aggregation. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We first try to introduce some new chemical approaches to prevent the misfolding or aggregation of specific proteins via direct binding interactions. We then start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organ proteostasis. © 2016 BioFactors, 43(6):737-759, 2017.

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“…23,24 Studies also showed that compounds having α, β-unsaturated moiety or the thiazolopyrimidine core structure are capable of inhibiting AChE. 23,25–27 Moreover, the N -benzylpiperidine moiety is a structure found in donepezil, a FDA-approved drug for treatment of mild to moderate AD. 28 The crystal structure of AChE in complex with donepezil, revealed a π-π stacking as well as hydrogen bonding interaction of N -benzylpiperidine to the active site of AChE.…”

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Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors

Basiri

Xiao

McCarthy

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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Alzheimer’s disease (AD) is a neurodegenerative disorder affecting 35 million people worldwide. A common strategy to improve the well-being of AD patients consists on the inhibition of acetylcholinesterase with the concomitant increase of the neurotransmitter acetylcholine at cholinergic synapses. Two series of unreported N-benzylpiperidines 5(a–h) and thiazolopyrimidines 9(a–q) molecules were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activities. Among the newly synthesized compounds, 5h, 9h, 9j, and 9p displayed higher AChE enzyme inhibitory activities than the standard drug, galantamine, with IC50 values of 0.83, 0.98, and 0.73 μM, respectively. Cytotoxicity studies of 5h, 9h, 9j, 9n and 9p on human neuroblastoma cells SH-SY5Y, showed no toxicity up to 40 μM concentration. Molecular docking simulations of the active compounds 5h and 9p disclosed the crucial role of π-π-stacking in their binding interaction to the active site AChE enzyme. The presented compounds have potential as AChE inhibitors and potential AD drugs.

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Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: Characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity

Cited by 50 publications

References 36 publications

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases

Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors

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