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Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier

[ Vol. 15 , Issue. 12 ]

Author(s):

Slavka Hamulakova*, Ladislav Janovec, Ondrej Soukup, Daniel Jun, Jana Janockova, Martina Hrabinova, Vendula Sepsova and Kamil Kuca*   Pages 1096 - 1105 ( 10 )

Abstract:


Background: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets.

Methods: All compounds were tested for their inhibitory activity on human AChE/BChE. The EllmanĀ“s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively.

Results: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier.

Conclusion: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.

Keywords:

Alzheimer`s disease, coumarin, acetylcholinesterase inhibitors, synthesis, cholinesterases, docking.

Affiliation:

Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, P.J. Safarik University, Moyzesova 11, SK-041 67 Kosice, Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, P.J. Safarik University, Moyzesova 11, SK-041 67 Kosice, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Department of Toxicology and Military Pharmacy, Faculty Military Helath Sciences, University of Defense, Trebesska 1575, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Department of Toxicology and Military Pharmacy, Faculty Military Helath Sciences, University of Defense, Trebesska 1575, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove



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