Twelve derivatives 1a-1m of the β-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 3β (GSK-3β) 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-3β 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.

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

Centro de Investigaciones Biológicas CSIC Avenida Ramiro de Maeztu 9 28040 Madrid Spain

Deaprtment of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentská 95 532 10 Pardubice Czech Republic

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

Department for Life Quality Studies University of Bologna Corso D'Augusto 237 47921 Rimini Italy

Department of Analytical Chemistry Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Medicinal Biochemistry Faculty of Medicine Charles University Zborovská 2089 500 03 Hradec Králové Czech Republic

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

Department of Pharmacognosy Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Toxicoloxy and Military Pharmacy Faculty of Military Health Sciences University of Defence Třebešská 1575 500 05 Hradec Králové Czech Republic

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Semisynthetic Derivatives of Selected Amaryllidaceae Alkaloids as a New Class of Antimycobacterial Agents

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