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

Molecules

Katarina Spilovska⁴  Jan Korabecny⁴  Jan Kral³  Anna Horova⁴  Kamil Musilek⁴  Ondrej Soukup²  Lucie Drtinova⁴  Zuzana Gazova¹  Katarina Siposova¹ 

[1] Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Kosice, Slovakia; E-Mails:;University Hospital, Biomedicinal Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; E-Mail:;Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; E-Mail:;Department of Toxicology, Trebesska 1575, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic; E-Mails:

关键词: 7-MEOTA;    amantadine;    inhibitor;    Alzheimer’s disease;    acetylcholinesterase;    butyrylcholinesterase;   

DOI  :  10.3390/molecules18022397

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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