Hamulakova_2018_Curr.Alzheimer.Res_15_1096

Reference

Title : Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier - Hamulakova_2018_Curr.Alzheimer.Res_15_1096
Author(s) : Hamulakova S , Janovec L , Soukup O , Jun D , Janockova J , Hrabinova M , Sepsova V , Kuca K
Ref : Curr Alzheimer Res , 15 :1096 , 2018
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 Ellman 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 micromol) and 7d towards hAChE (IC50 = 0.32 micromol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 micromol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 micromol). Moreover, hybrid 5d and 7c could penetrate the CNS.

PubMedSearch : Hamulakova_2018_Curr.Alzheimer.Res_15_1096
PubMedID: 29992880

Related information

Citations formats

Hamulakova S, Janovec L, Soukup O, Jun D, Janockova J, Hrabinova M, Sepsova V, Kuca K (2018)
Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier
Curr Alzheimer Res 15 :1096

Hamulakova S, Janovec L, Soukup O, Jun D, Janockova J, Hrabinova M, Sepsova V, Kuca K (2018)
Curr Alzheimer Res 15 :1096