Molecules 2013, 18(2), 2397-2418; doi:10.3390/molecules18022397
Article

7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies

1email, 1,2email, 3email, 1email, 1,2,4email, 2email, 1email, 5email, 5,6email and 2,7,* email
Received: 14 January 2013; in revised form: 24 January 2013 / Accepted: 4 February 2013 / Published: 20 February 2013
(This article belongs to the Section Medicinal Chemistry)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: 7-MEOTA; amantadine; inhibitor; Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase
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MDPI and ACS Style

Spilovska, K.; Korabecny, J.; Kral, J.; Horova, A.; Musilek, K.; Soukup, O.; Drtinova, L.; Gazova, Z.; Siposova, K.; Kuca, K. 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies. Molecules 2013, 18, 2397-2418.

AMA Style

Spilovska K, Korabecny J, Kral J, Horova A, Musilek K, Soukup O, Drtinova L, Gazova Z, Siposova K, Kuca K. 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies. Molecules. 2013; 18(2):2397-2418.

Chicago/Turabian Style

Spilovska, Katarina; Korabecny, Jan; Kral, Jan; Horova, Anna; Musilek, Kamil; Soukup, Ondrej; Drtinova, Lucie; Gazova, Zuzana; Siposova, Katarina; Kuca, Kamil. 2013. "7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies." Molecules 18, no. 2: 2397-2418.

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