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

Author:

Mamun Abdullah AlORCID,Pidaný FilipORCID,Hulcová Daniela,Maříková JanaORCID,Kučera TomášORCID,Schmidt MonikaORCID,Catapano Maria CarmenORCID,Hrabinová MartinaORCID,Jun DanielORCID,Múčková LubicaORCID,Kuneš Jiří,Janoušek JiříORCID,Andrýs Rudolf,Nováková LucieORCID,Peřinová Rozálie,Maafi NegarORCID,Soukup OndřejORCID,Korábečný JanORCID,Cahlíková LucieORCID

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.

Funder

Univerzita Karlova v Praze

Czech Science Foundation

Univerzita Hradec Králové

Ministerstvo Školství, Mládeže a Tělovýchovy

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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