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

Eur J Med Chem. 2018 Apr 25:150:292-306. doi: 10.1016/j.ejmech.2018.02.083.

V Hepnarova ¹, J Korabecny ¹, L Matouskova ², P Jost ¹, L Muckova ², M Hrabinova ¹, N Vykoukalova ³, M Kerhartova ⁴, T Kucera ², R Dolezal ⁵, E Nepovimova ⁶, K Spilovska ⁷, E Mezeiova ⁷, N L Pham ¹, D Jun ¹, F Staud ³, D Kaping ⁸, K Kuca ⁶, O Soukup ⁹

Affiliations

1 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
2 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
3 Department of Pharmacology and Toxicology, Charles University, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
4 Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
5 Biomedical Research Centre, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
6 Biomedical Research Centre, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
7 Biomedical Research Centre, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
8 National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
9 Biomedical Research Centre, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.

PMID: 29533874 DOI: 10.1016/j.ejmech.2018.02.083

Abstract

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.

Keywords

7-Methoxytacrine; Acetylcholinesterase; Acetylcholinesterase inhibitor; Alzheimer's disease; BQCA; Butyrylcholinesterase; Multi-target directed ligands; Positive allosteric modulator of muscarinic receptor; Tacrine.

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