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6-Methoxy-1-Tetralone Derivatives Bearing an N-Arylpyridinium Moiety As Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Study Publisher



Chehardoli G1 ; Gholamhoseini P2 ; Ebadi A1 ; Ziaei M2 ; Akbarzadeh T3, 4 ; Saeedi M4, 5 ; Mahdavi M6 ; Khoshneviszadeh M7 ; Najafi Z2
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Source: ChemistrySelect Published:2022


Abstract

A novel series of 6-methoxy-1-tetralone derivatives bearing N-aryl pyridinium moiety were designed, synthesized, and evaluated as acetyl and butyrylcholinesterase inhibitors. The designed derivatives inhibited acetylcholinesterase (AChE) with IC50 values of 0.025–23.743 μM and butyrylcholinesterase (BChE) with IC50 values of 0.716–20.588 μM. The synthesized compounds were divided into two series. Derivatives containing N-benzyl moieties generally were more potent anti-AChE and anti-BChE agents than compounds with N-alkylphthalimide groups. Among them, the compound (E)-1-Benzyl-3-((6-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (5 a) and compound (E)-1-(3-Chlorobenzyl)-3-((6-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (5 d) exhibited significant inhibitory activity against AChE and BChE with IC50 values of 0.025 and 0.716 μM in comparison to donepezil as a reference drug (0.029 and 0.948 μM, respectively). The results of kinetic and molecular modeling studies demonstrated that the synthesized compounds 5 a and 5 d derivatives can act as mixed and dual binding inhibitors, and bind to both CAS and PAS of AChE and BChE enzymes. Among the assessed compounds, the compound 5 a indicated significant neuroprotection against H2O2-induced cell death in PC12 cells. So, these findings indicate the therapeutic potential of 6-methoxy-1-tetralone derivatives bearing N-aryl pyridinium moiety derivatives as anti-AD agents. © 2022 Wiley-VCH GmbH.
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