Molecular Docking and Recent Advances in the Design and Development of Cholinesterase Inhibitor Scaffolds: Coumarin Hybrids

Hasan, Aso Hameed; Amran, Syazwani Itri; Hussain, Faiq H. S.; Jaff, Baram Ahmed; Jamalis, Joazaizulfazli

doi:10.1002/slct.201903607

Cited by 14 publications

(12 citation statements)

References 126 publications

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“…The coumarin cores of those hybrids can occupy the peripheral anionic site (PAS) of AChE. [15,18,19] 1,3,5-Triazine is a six-membered aromatic ring compound containing three nitrogen atoms which possesses a wide range of biological activities such as anti-inflammatory, antimicrobial, anticancer, antiviral, and antimalarial. [20][21][22][23][24][25][26][27][28] Numerous 1.3,5triazine-containing molecules are capable of modulating single as well as multiple pathological factors involved in AD due to the potential for multiple biological effects of 1.3,5-triazine.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

Zhang,

Wang,

Zou

et al. 2024

ChemistrySelect

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A series of coumarin‐1,3,5‐triazine derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors. The structures of those compounds were characterized by IR, NMR, HRMS, HPLC, and X‐ray. The structures of those coumarin‐1,3,5‐triazine derivatives are the mixtures of two geometric isomers. The 1H‐NMR of compound 3 g without coumarin structure and its hydrochloride and single crystal structure of compound 3 g were studied to prove the coumarin‐1,3,5‐triazine derivatives are the mixtures of two geometric isomers. The acetylcholinesterase and butyrylcholinesterase inhibitory activities of the synthesized compounds were determinated by Ellman's method. The results showed that all the compounds could inhibit acetylcholinesterase selectively. Among them, compound 3 b was found to have the strongest inhibitory effect on acetylcholinesterase with an IC50 value of 0.018 μM, which was closest to the IC50 of the positive control donepezil (IC50=0.016 μM). Enzyme kinetic studies indicate that this compound inhibited acetylcholinesterase with a mixed mode. Molecular docking, molecular dynamics simulation study and binding free energy calculation experiments demonstrated that compound 3 b could stably interact with key amino acids in the catalytically active site and the peripheral anion site of acetylcholinesterase. According to the results, compound 3 b demonstrates promising potential as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

“…Novel AChE inhibitors for the treatment of AD are regularly created using the structure of coumarin hybrids as a template. The coumarin cores of those hybrids can occupy the peripheral anionic site (PAS) of AChE [15,18,19] …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

Zhang,

Wang,

Zou

et al. 2024

ChemistrySelect

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“…In addition, studies have proven that compounds with tricyclic and heterocyclic systems can interact with each CAS and PAS of ChEs through hydrophobic interactions. [ 14 ] To interact with the PAS region, a heterocyclic system that can be used instead of indanone in donepezil agent was needed. The benzimidazole scaffold represents a privileged structure because of its presence in inhibitory potential against AD.…”

Section: Introductionmentioning

confidence: 99%

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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“…In addition, studies have proven that compounds with tricyclic and heterocyclic systems can interact with each catalytic anionic site (CAS) and peripheral anionic site of ChEs through hydrophobic interactions. [ 25 ] The benzofuran scaffold represents a privileged structure because of its presence in many biologically active natural and therapeutic products. The biological activities of benzofuran derivatives include antimicrobial, anti‐inflammatory, antitubercular, antitumor, cytotoxic, antiplasmodial, antioxidant, and AChE inhibitory.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of novel chalcone derivatives and evaluation of their inhibitory activities against acetylcholinesterase

Ceyhun

Karaca

Osmaniye

et al. 2021

Archiv der Pharmazie

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According to the cholinergic hypothesis, an increase in the acetylcholine level in Alzheimer's disease patients relatively slows down the symptoms of the disease. The most commonly used drug, donepezil, is a cholinesterase inhibitor. In this study, 12 new chalcones (2a–l) were designed and synthesized. In biological activity studies, the acetylcholinesterase (AChE) and butyrylcholinesterase inhibitory potentials of all compounds were evaluated using the in vitro Ellman method. The biological evaluation showed that compounds 2d, 2f, 2j, and 2l displayed significant activity against AChE. The compounds 2d, 2f, 2j, and 2l displayed IC50 values of 0.042, 0.024, 0.053, and 0.033 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also displayed significant inhibition of AChE. The inhibitory activities of these compounds for β‐amyloid plaque aggregation were investigated. The enzyme kinetic study was performed to observe the effect of the most active compound 2f on the substrate–enzyme relationship, and a mixed‐type inhibition of AchE was determined. Further, docking simulation also revealed that these compounds (2d, 2f, 2j, and 2l) interacted with the enzyme active site in a similar manner to donepezil. The most active derivative, compound 2f, interacted with the amino acids Trp286, Phe295, Tyr341, Trp86, and Glu202.

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Molecular Docking and Recent Advances in the Design and Development of Cholinesterase Inhibitor Scaffolds: Coumarin Hybrids

Cited by 14 publications

References 126 publications

Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

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

Design and synthesis of novel chalcone derivatives and evaluation of their inhibitory activities against acetylcholinesterase

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