Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer’s Disease
Eliška Kohelová,
Rozálie Peřinová,
Negar Maafi,
Jan Korábečný,
Daniela Hulcová,
Jana Maříková,
Tomáš Kučera,
Loreto Martínez González,
Martina Hrabinova,
Katarina Vorčáková,
Lucie Nováková,
Angela De Simone,
Radim Havelek,
Lucie Cahlíková
Affiliations
Eliška Kohelová
ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Rozálie Peřinová
ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Negar Maafi
ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Jan Korábečný
Department of Toxicoloxy and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 500 05 Hradec Králové, Czech Republic
Daniela Hulcová
ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Jana Maříková
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Tomáš Kučera
Department of Toxicoloxy and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 500 05 Hradec Králové, Czech Republic
Loreto Martínez González
Centro de Investigaciones Biológicas-CSIC, Avenida Ramiro de Maeztu 9, 28040 Madrid, Spain
Martina Hrabinova
Department of Toxicoloxy and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 500 05 Hradec Králové, Czech Republic
Katarina Vorčáková
Deaprtment of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 95, 532 10 Pardubice, Czech Republic
Lucie Nováková
Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Angela De Simone
Department for Life Quality Studies, University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
Radim Havelek
Department of Medicinal Biochemistry, Faculty of Medicine, Charles University, Zborovská 2089, 500 03 Hradec Králové, Czech Republic
Lucie Cahlíková
ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
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.