7-Methoxytacrine-adamantylamine Heterodimers As Cholinesterase Inhibitors in Alzheimer's Disease Treatment--synthesis, Biological Evaluation and Molecular Modeling Studies

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2013 Feb 23

PMID 23429378

Citations 14

Authors

Katarina Spilovska

Jan Korabecny

Jan Kral

Anna Horova

Kamil Musilek

Ondrej Soukup

Lucie Drtinova

Zuzana Gazova

Katarina Siposova

Kamil Kuca

Affiliations

Soon will be listed here.

Abstract

A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

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