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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

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 and 2,7,*
1 Department of Toxicology, Trebesska 1575, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic 2 University Hospital, Biomedicinal Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic 3 Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic 4 Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic 5 Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Kosice, Slovakia 6 Faculty of Sciences, Institute of Chemistry, P. J. Safarik University, Srobarova 2, 041 54 Kosice, Slovakia 7 Centre of Advanced Studies, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
* Author to whom correspondence should be addressed.
Received: 14 January 2013 / Revised: 24 January 2013 / Accepted: 4 February 2013 / Published: 20 February 2013
(This article belongs to the Section Medicinal Chemistry)
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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 7-MEOTA; amantadine; inhibitor; Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase
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.

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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.

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