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.

ADINACO Research Group Department of Pharmaceutical Botany Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic

Department of Analytical Chemistry Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Bioorganic and Organic Chemistry Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Králové Rokitanského 62 500 03 Hradec Králové Czech Republic

Department of Pharmacognosy Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

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Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Recent Progress on Biological Activity of Amaryllidaceae and Further Isoquinoline Alkaloids in Connection with Alzheimer's Disease