Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

Lukas Hroch, Patrick Guest, Ondrej Benek, Ondrej Soukup, Jana Janockova, Rafael Dolezal, Kamil Kuca, Laura Aitken, Terry K. Smith, Frank Gunn-Moore, Dominykas Zala, Rona R. Ramsay, Kamil Musilek

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)
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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAOB with IC50 values of 6.34 μM and 0.30 μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.
Original languageEnglish
Pages (from-to)1143-1152
Number of pages10
JournalBioorganic & Medicinal Chemistry
Volume25
Issue number3
Early online date27 Dec 2016
DOIs
Publication statusPublished - 1 Feb 2017

Keywords

  • Alzheimer's disease (AD)
  • Monoamine oxidase (MAO)
  • Amyloid-beta peptide (Aβ)
  • Mitochondrial amyloid-binding alcohol dehydrogenase (ABAD)
  • 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10)
  • Horseradish peroxidase (HRP)

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