The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease

Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented h...

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Published in:	European journal of medicinal chemistry Vol. 150; pp. 292 - 306
Main Authors:	Hepnarova, V., Korabecny, J., Matouskova, L., Jost, P., Muckova, L., Hrabinova, M., Vykoukalova, N., Kerhartova, M., Kucera, T., Dolezal, R., Nepovimova, E., Spilovska, K., Mezeiova, E., Pham, N.L., Jun, D., Staud, F., Kaping, D., Kuca, K., Soukup, O.
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 25-04-2018
Subjects:	7-Methoxytacrine Acetylcholinesterase Acetylcholinesterase inhibitor Alzheimer's disease BQCA Butyrylcholinesterase Multi-target directed ligands Positive allosteric modulator of muscarinic receptor Tacrine Positive allosteric modulator of muscarinic receptor Acetylcholinesterase inhibitor BQCA 7-Methoxytacrine Acetylcholinesterase Butyrylcholinesterase Multi-target directed ligands Alzheimer's disease Tacrine
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Summary:	Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 μM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD. [Display omitted] •Tacrine-BQCA hybrids inhibit both cholinesterases in nanomolar concentrations.•Tacrine moiety ensures interaction with cholinesterases.•Tacrine-BQCA hybrids effectively inhibit muscarinic M1 receptor.•Some tacrine-BQCA derivatives are predicted to cross blood-brain barrier.
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2018.02.083