Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer's Disease

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 7; p. 1307
• Main Authors: Kohelová, Eliška, Peřinová, Rozálie, Maafi, Negar, Korábečný, Jan, Hulcová, Daniela, Maříková, Jana, Kučera, Tomáš, Martínez González, Loreto, Hrabinova, Martina, Vorčáková, Katarina, Nováková, Lucie, De Simone, Angela, Havelek, Radim, Cahlíková, Lucie
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.04.2019; MDPI
• Subjects: Acetylcholinesterase; Alkaloids; Alzheimer Disease - metabolism; Alzheimer's disease; Amaryllidaceae; Amaryllidaceae - chemistry; Amaryllidaceae - metabolism; Amaryllidaceae Alkaloids - chemistry; Amaryllidaceae Alkaloids - metabolism; Blood-brain barrier; Blood-Brain Barrier - metabolism; butyrylcholinesterase; Cyclin-dependent kinases; Cytotoxicity; Dementia; docking studies; Drugs; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - metabolism; glycogen synthase kinase-3β inhibition; Glycogens; haemanthamine; Humans; Inspection; Kinases; Ligands; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Structure; Permeability; Phenanthridines - chemistry; Phenanthridines - metabolism; Phosphorylation; Proteins; Structure-Activity Relationship; docking studies; butyrylcholinesterase; Alzheimer’s disease; glycogen synthase kinase-3β inhibition; acetylcholinesterase; haemanthamine; Amaryllidaceae
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24071307

Twelve derivatives - 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- -(2-methylbenzoyl)-haemanthamine ( ) and 11- -(4-nitrobenzoyl)-haemanthamine ( ), revealed the most intriguing profile, both being acetylcholinesterase ( AChE) 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 AChE and BuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.