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In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier

1
ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
2
Biomedical Research Center, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic
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Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Třebešská 1575, 500 01 Hradec Králové, Czech Republic
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Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Králové, Rokitanského 62, 50003 Hradec Králové, Czech Republic
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Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 95, 532 10 Pardubice, Czech Republic
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Centro de Investigaciones Biológicas, Avenida Ramiro de Maetzu 9, 280 40 Madrid, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Molecules 2019, 24(7), 1340; https://doi.org/10.3390/molecules24071340
Received: 18 March 2019 / Revised: 31 March 2019 / Accepted: 4 April 2019 / Published: 5 April 2019
(This article belongs to the Section Natural Products Chemistry)
In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman’s spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood–brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer’s disease. View Full-Text
Keywords: (+)-thalictricavine; (+)-canadine; cholinesterases; kinetic study; molecular docking; blood–brain barrier permeability (+)-thalictricavine; (+)-canadine; cholinesterases; kinetic study; molecular docking; blood–brain barrier permeability
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Chlebek, J.; Korábečný, J.; Doležal, R.; Štěpánková, Š.; Pérez, D.I.; Hošťálková, A.; Opletal, L.; Cahlíková, L.; Macáková, K.; Kučera, T.; Hrabinová, M.; Jun, D. In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier. Molecules 2019, 24, 1340.

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