Design, synthesis, <i>in vitro</i> and <i>in vivo</i> evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease

Mo, Jun; Chen, Tingkai; Yang, Hongyu; Guo, Yan; Li, Qi; Qiao, Yuting; Lin, Hongzhi; Feng, Feng; Liu, Wenyuan; Chen, Yao; Liu, Zongliang; Sun, Haopeng

doi:10.1080/14756366.2019.1699553

Cited by 20 publications

(9 citation statements)

References 30 publications

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“…On one hand, we speculate that methyl occupies the pocket of the active site and interacts with amino acid residues to increase inhibitory activity. On the other hand, Sulfonamide moiety is very important for maintaining ChEs inhibitory activity, which may be related to the bond angle between Sulfonamide and molecules [33].…”

Section: Ache and Bche Inhibitory Activity Of The Target Moleculesmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

et al. 2020

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A series of novel compounds 6a–h, 8i–1, 10s–v, and 16a–d were synthesized and evaluated, together with the known analogs 11a–f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound 8i showed the strongest inhibitory effect on both AChE (eeAChE IC50 = 0.39 μM) and BChE (eqBChE IC50 = 0.28 μM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound 8i bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound 8i is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer’s disease (anti-AD) agents. In summary, these data suggest that compound 8i is a promising multipotent agent for the treatment of AD.

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Section: Ache and Bche Inhibitory Activity Of The Target Moleculesmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

et al. 2020

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“…Structure of Benzylpiperidine derrivatives modified from 15b and 15j. 73 Benzylpiperidine linked dimethylbenzimidazolinone derivatives are similar to donepezil and were theorized to have a comparative mechanism in interacting with tryptophan at the binding sites of ACh through pi-stacking. 73 The IC50 value of these agents towards AChE ranges from 0.39 to 38uM.…”

Section: Dimethylbenzimidazolinonementioning

confidence: 99%

“…73 Benzylpiperidine linked dimethylbenzimidazolinone derivatives are similar to donepezil and were theorized to have a comparative mechanism in interacting with tryptophan at the binding sites of ACh through pi-stacking. 73 The IC50 value of these agents towards AChE ranges from 0.39 to 38uM. 73 The most potent of these compounds being referred to as Compounds 15b and 15j (Figure 23).…”

Section: Dimethylbenzimidazolinonementioning

confidence: 99%

“…73 The IC50 value of these agents towards AChE ranges from 0.39 to 38uM. 73 The most potent of these compounds being referred to as Compounds 15b and 15j (Figure 23). 73 Though no clinical testing has been performed yet, these compounds may have the potential of becoming an agent for the treatment of AD .…”

Section: Dimethylbenzimidazolinonementioning

confidence: 99%

“…73 The most potent of these compounds being referred to as Compounds 15b and 15j (Figure 23). 73 Though no clinical testing has been performed yet, these compounds may have the potential of becoming an agent for the treatment of AD . Natural products and their derivatives overall has been long investigated and may present potential compound(s) that can be developed for AD treatment.…”

Section: Dimethylbenzimidazolinonementioning

confidence: 99%

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Acetylcholinesterase Inhibitors for Alzheimer’s disease: Past, Present, and Potential Future

Truong

Quiroz

Priefer

2020

MRAJ

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Alzheimer’s Diseases (AD) is a neurodegenerative disorder characterized by progressive neuronal loss leading to cognitive decline. Although there is yet to be a cure nor a way to reverse the neuronal damage, there are current treatments to amend some of the cognitive symptoms associated with AD. Acetylcholinesterase inhibitors (AChEi) are the primary agents of choice and have had profound implications throughout the past decades. AChEi such as donepezil, rivastigmine, and galantamine mediates and increases cholinergic activities in the central nervous system (CNS), and have been shown to improve and preserve cognition in AD patients. Beyond the current drugs on the market, investigational discoveries continue to explore the potential of safer and more efficacious AChEi agents for the treatment of AD. There have been quite a few challenges, given the high failure rates. Yet, these very trials and studies have been a fundamental step towards better understanding the treatments of AD and have provided some insight on the potential to surpass what is currently available.

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Design, synthesis, biological activity, molecular docking, and molecular dynamics of novel benzimidazole derivatives as potential AChE/MAO‐B dual inhibitors

Osmaniye

Evren

Sağlık

et al. 2021

Archiv der Pharmazie

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To develop new acetylcholinesterase (AChE)–monoamine oxidase‐B (MAO‐B) dual inhibitors against Alzheimer's disease, the benzimidazole ring, which has a propargyl side chain with previously proven selective MAO‐B inhibitory activity, was used as the main structure. Moreover, like donepezil, it was thought that the enzyme AChE would provide π–π interactions with the peripheral anionic side in this structure. Piperazine derivatives were chosen for the cationic active site. The synthesis of the compounds was carried out in five steps. The structures of the compounds were determined using 1H‐NMR (nuclear magnetic resonance), 13C‐NMR, and high‐resolution mass spectrometry spectroscopic methods. First, the in vitro AChE, butyrylcholinesterase (BChE), MAO‐A, and MAO‐B inhibitory potentials of the obtained compounds were investigated. As a result of activity tests, compounds 5b, 5e, 5g, and 5h showed inhibitory activity against AChE; compounds 5e and 5g showed inhibitory activity against MAO‐B. None of the compounds showed inhibitory activity against BChE or MAO‐A. Compounds 5e and 5g showed dual inhibition. Among these compounds, compound 5g had inhibition potential similar to that of donepezil and selegiline. For compound 5g, further kinetic studies and Aβ‐plaque inhibitory potentials were investigated using in vitro methods. Molecular docking studies were performed using both AChE and hMAO‐B crystals to elucidate the compound's interactions with the enzyme active site. The binding modes of the compound on AChE were fully elucidated by molecular dynamics studies.

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Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease

Cited by 20 publications

References 30 publications

Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

Acetylcholinesterase Inhibitors for Alzheimer’s disease: Past, Present, and Potential Future

Design, synthesis, biological activity, molecular docking, and molecular dynamics of novel benzimidazole derivatives as potential AChE/MAO‐B dual inhibitors

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