Design, synthesis and in vitro evaluation of indolotacrine analogues as multi-target-directed ligands for the treatment of Alzheimer’s disease

Ondrej Benek, Ondrej Soukup, Marketa Pasdiorova, Lukas Hroch, Vendula Sepsova, Petr Jost, Martina Hrabinova, Daniel Jun, Kamil Kuca, Dominykas Zala, Rona R. Ramsay, José Marco-Contelles, Kamil Musilek

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

In this study, novel indolotacrine analogues have been designed, synthesized and evaluated as potential drugs for the treatment of Alzheimer’s disease. Based on a multi-target-directed ligand approach, novel compounds have been designed to act simultaneously as cholinesterase and monoamine oxidase (MAO) inhibitors. Prepared compounds were also evaluated for their antioxidant, cytotoxic, hepatotoxic and permeability (Blood-Brain Barrier penetration) properties. Indolotacrine 9b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment being a potent inhibitor of acetylcholinesterase (IC50 = 1.5 µM), butyrylcholinesterase (IC50 = 2.4 µM) and monoamine oxidase A (IC50 = 0.49 µM) and a weak inhibitor of monoamine oxidase B (IC50 = 53.9 µM). Although its cytotoxic (IC50 = 5.5 ± 0.4 µM) and hepatotoxic (IC50 = 1.22 ± 0.11 µM) profile is not as good as the standard 7-methoxytacrine (IC50 = 63 ± 4 µM and IC50 = 11.50 ± 0.77 µM respectively), the overall improvement in the inhibitory activities and potential to cross blood-brain barrier make indolotacrine 9b a promising lead compound for further development and investigation.

Original languageEnglish
Pages (from-to)1264 -1269
Number of pages6
JournalChemMedChem
Volume11
Issue number12
Early online date2 Oct 2015
DOIs
Publication statusPublished - 20 Jun 2016

Keywords

  • Alzheimer's disease
  • Cholinesterase
  • Cytotoxicity
  • Inhibitors
  • Monoamine oxidase
  • Multi-target-directed ligands
  • MTDLs

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