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: [email protected].
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.