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Derivatives of the beta-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer's Disease
Authors: Kohelova Eliska | Perinova Rozalie | Maafi Negar | Korabecny Jan | Hulcova Daniela | Marikova Jana | Kucera Tomas | Martinez Gonzalez Loreto | Hrabinova Martina | Svrčková Katarína | Novakova Lucie | De Simone Angela | Havelek Radim | Cahlikova Lucie
Year: 2019
Type of publication: článek v odborném periodiku
Name of source: Molecules
Publisher name: MDPI AG (Multidisciplinary Digital Publishing Institute)
Place: Basel
Page from-to: "1307-1"-"1307-18"
Titles:
Language Name Abstract Keywords
cze Deriváty beta-Crinane Amaryllidaceae Alkaloid Haemanthamine jako vícecílové cílené ligandy pro Alzheimerovu chorobu Bylo vyvinuto dvanáct derivátů la-lm alkaloidního hematoaminu beta-krinanu. Všechny semisyntetické deriváty byly studovány na inhibiční potenciál proti acetylcholinesteráze i butyrylcholinesteráze. Kromě toho byla v aktivních derivátech hodnocena inhibiční schopnost glykogen syntázy kinázy 3 beta (GSK-3 beta). Abychom odhalili dostupnost léčiv pro CNS, objasnili jsme potenciál vybraných derivátů proniknout hematoencefalickou bariérou (BBB). Dvě sloučeniny, jmenovitě 11-O- (2-methylbenzoyl) -haemanthamin (1j) a 11-O- (4-nitrobenzoyl) -haemanthamin (1m), odhalily nejzajímavější profil, obě jsou inhibitory acetylcholinesterázy (hAChE) na mikromolárním v měřítku, s inhibičními vlastnostmi GSK-3 beta a předpovězenou permeací BBB. Data in vitro byla dále potvrzena podrobnou inspekcí věrohodných vazebných režimů sloučenin v aktivních místech hAChE a hBuChE, což nás vedlo k poskytnutí strukturálních determinant odpovědných za aktivitu vůči těmto enzymům. haemanthamin; Amaryllidaceae; Alzheimerova choroba; acetylcholinesteráza; butyrylcholinesteráza; inhibice glykogen syntázy kinázy-3 beta; dokovací studie
eng Derivatives of the beta-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer's Disease 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. haemanthamine; Amaryllidaceae; Alzheimer's disease; acetylcholinesterase; butyrylcholinesterase; glycogen synthase kinase-3 beta inhibition; docking studies

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