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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

AA. Mamun, F. Pidaný, D. Hulcová, J. Maříková, T. Kučera, M. Schmidt, MC. Catapano, M. Hrabinová, D. Jun, L. Múčková, J. Kuneš, J. Janoušek, R. Andrýs, L. Nováková, R. Peřinová, N. Maafi, O. Soukup, J. Korábečný, L. Cahlíková

. 2021 ; 22 (15) : . [pub] 20210802

Language English Country Switzerland

Document type Evaluation Study, Journal Article

Persistent link   https://www.medvik.cz/link/bmc21025167

Grant support
SVV UK 260 548, 260 547; Progres/UK Q42 Univerzita Karlova v Praze
20-29633J Czech Science Foundation
VT2019-2021 Univerzita Hradec Králové
CZ.02.1.01/0.0/0.0/16_019/0000841 Ministerstvo Školství, Mládeže a Tělovýchovy
SAF2016-76693-R MICU
LM2015042 CESNET
LM2015085 CERIT Scientific Cloud

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.

References provided by Crossref.org

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