Journal
MOLECULES
Volume 24, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/molecules24071307
Keywords
haemanthamine; Amaryllidaceae; Alzheimer's disease; acetylcholinesterase; butyrylcholinesterase; glycogen synthase kinase-3 beta inhibition; docking studies
Funding
- Charles University [178518, SVV UK 260 412, 260 401, Progres/UK Q40, Progres/UK Q42]
- MH CZ - DRO (University Hospital Hradec Kralove) [00179906]
- Long-term development plan (Faculty of Military Health Sciences)
- Pre-application research into innovative medicines and medical technologies project - European Union [CZ. 02.1.01/0.0/0.0/18_069/0010046]
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Twelve derivatives 1a-1m of the beta-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3 beta (GSK-3 beta) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3 beta inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.
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