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Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease.

ABSTRACT: To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH3 > -CH3 > -Cl (-Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.

SUBMITTER: Wu C 

PROVIDER: S-EPMC8386747 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Structure-activity relationship, <i>in vitro</i> and <i>in vivo</i> evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease.

Wu Chengyao C   Zhang Guijuan G   Zhang Zai-Wei ZW   Jiang Xia X   Zhang Ziwen Z   Li Huanhuan H   Qin Hua-Li HL   Tang Wenjian W  

Journal of enzyme inhibition and medicinal chemistry 20211201 1

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound <b>A10</b> was identified as a selective BuChE inhibitor (IC<sub>50</sub> = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) <i>o</i>- > <i>m</i>- > <i>p</i>-; -OCH<sub>3</sub> > -CH<sub>3</sub> > -Cl (-Br) for <i>δ</i>-aryl; (ii) α-Br > α-Cl, α-I. Compound <b>A10</b> exhibi  ...[more]

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