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
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.