Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil

Greunen, Divan G. van; Cordier, Werner; Nell, Margo; Westhuyzen, Christiaan W. van der; Steenkamp, Vanessa; Panayides, Jenny‐Lee; Riley, Darren L.

doi:10.1016/j.ejmech.2016.10.036

Cited by 39 publications

(21 citation statements)

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“…To investigate the interaction mode of compounds 1 and 1q with AChE, a molecular modeling study was carried out using Molecular Operating Environment ( moe ) software and the PDB structure of 1EVE was taken from the RCSB Protein Data Bank for the docking procedure. Previous studies showed that two methoxy groups of donepezil interacted with Trp286 of acetylcholinesterase through hydrogen bond . In the present study, the methoxy group at the C7 position of compound 1 interacted with Trp286 to form a hydrogen bond, while the methoxy group at the C8 position could not form a hydrogen bond with Trp286 due to steric hindrance (Figure b).…”

Section: Resultssupporting

confidence: 43%

Design, synthesis, biological evaluation, and docking study of 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

Wang

Zheng

et al. 2017

Chem Biol Drug Des

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A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti-AChE activity with an IC value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti-Alzheimer's disease agents.

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Section: Resultssupporting

confidence: 43%

Design, synthesis, biological evaluation, and docking study of 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

Wang

Zheng

et al. 2017

Chem Biol Drug Des

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“…), again emphasizing the importance of the crystal structure of the human enzyme for the design of improved lead compounds based on donepezil (van Greunen et al . ).…”

Section: Structural Studies On Human Acetylcholinesterasementioning

confidence: 97%

Recent developments in structural studies on acetylcholinesterase

Silman

Sussman

2017

Journal of Neurochemistry

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This review focuses on several recent developments concerning structure-function relationships in vertebrate acetylcholinesterase. These include studies on high-resolution structures of human acetylcholinesterase and its complexes; the first crystal structure of a snake venom acetylcholinesterase, in which open and closed states of the 'back door' are visualized; a powerful algorithm for redesigning proteins for enhanced expression in prokaryotic systems, as applied to human acetylcholinesterase, which has hitherto been an intractable target; in situ implementation of 'click chemistry' in crystalline acetylcholinesterase, which yields novel insights into the steric and dynamic changes involved in the reaction within the active-site gorge; and a study that demonstrates the effect of crystallization conditions on ligand alignment within a protein complex, in this case the methylene blue-Torpedo californica acetylcholinesterase complex, which highlights the relevance of the precipitant employed to structure-based drug design. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

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“…Additionally, nonhepatotoxicity, blood-brain barrier (BBB) permeability, a single daily dose, and the least side effects provide advantages for donepezil when compared to other AChE inhibitors [5]. Therefore, donepezil analogs have been studied more broadly [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Activity Evaluation of New Donepezil-Like Compounds Bearing Thiazole Ring for the Treatment of Alzheimer’s Disease

et al. 2020

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Alzheimer’s disease (AD) is a progressive and neurodegenerative disease that is primarily seen in the elderly population and is clinically characterized by memory and cognitive impairment. The importance of the disease has increased as a result of etiology of the disease having not yet been determined, an increase in patient population over the years, absence of radical treatment, high cost of treatment and care, and significant reduction in the quality of life of the patients, which have led researchers to direct more attention to this field. In a recent study, new indan-thiazolylhydrazone derivatives were designed and synthesized based on the chemical structure of the donepezil molecule, which is the most preferred and has the most appropriate response in the treatment of AD. The structures of the compounds were determined by 1H-NMR and 13C-NMR, and mass spectroscopic methods. Inhibition studies on the cholinesterase (ChE) enzymes and beta amyloid plaque inhibition test of the compounds were performed. Among the synthesized derivatives, compounds 2a, 2e, 2i, and 2l showed potent inhibitory activity on the AChE enzyme. Compound 2e was found to be the most active agent, with an IC50 value of 0.026 µM. The mechanism of AChE inhibition by compound 2e was studied using the Lineweaver-Burk plot, and the nature of inhibition was also determined to be mix-typed. Molecular docking studies were also carried out for compound 2e, which was found as the most potent agent within the AChE enzyme active site. Moreover, compounds 2a, 2e, 2i, and 2l displayed the ability to prevent beta amyloid plaque aggregation at varying rates. In addition, ADME (Absorption, Distribution, Metabolism, Elimination) parameters were evaluated for all synthesized compounds using the QikProp 4.8 software (Schrödinger Inc., NY, USA).

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Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil

Cited by 39 publications

References 39 publications

Design, synthesis, biological evaluation, and docking study of 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

Design, synthesis, biological evaluation, and docking study of 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

Recent developments in structural studies on acetylcholinesterase

Design, Synthesis, and Biological Activity Evaluation of New Donepezil-Like Compounds Bearing Thiazole Ring for the Treatment of Alzheimer’s Disease

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