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Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies.


ABSTRACT: Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

SUBMITTER: Mamun AA 

PROVIDER: S-EPMC8348983 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies.

Mamun Abdullah Al AA   Pidaný Filip F   Hulcová Daniela D   Maříková Jana J   Kučera Tomáš T   Schmidt Monika M   Catapano Maria Carmen MC   Hrabinová Martina M   Jun Daniel D   Múčková Lubica L   Kuneš Jiří J   Janoušek Jiří J   Andrýs Rudolf R   Nováková Lucie L   Peřinová Rozálie R   Maafi Negar N   Soukup Ondřej O   Korábečný Jan J   Cahlíková Lucie L  

International journal of molecular sciences 20210802 15


Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the <i>N</i>-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (<b>1</b>-<b>20</b>) structurally inspired from belladine-type Amaryllidace  ...[more]

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