Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease |
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| Authors: | Jan Korabecny Kamil Musilek Ondrej Holas Jiri Binder Filip Zemek Jan Marek Miroslav Pohanka Veronika Opletalova Vlastimil Dohnal Kamil Kuca |
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| Institution: | 1. Charles University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry and Drug Control, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;2. University of Defence, Faculty of Military Health Sciences, Department of Toxicology, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic;3. University of Jan Evangelista Purkynje, Faculty of Science, Department of Chemistry, Ceske Mladeze 8, 400 96 Usti nad Labem, Czech Republic;4. University of Defence, Faculty of Military Health Sciences, Centre of Advanced Studies, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic |
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| Abstract: | All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C6–C7 N-alkyl chains for cholinesterase inhibition. |
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