Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease

Hui Ju Tseng, Mei Hsiang Lin, Young Ji Shiao, Ying Chen Yang, Jung Chun Chu, Chun Yung Chen, Yi Ying Chen, Tony Eight Lin, Chih Jou Su, Shiow Lin Pan, Liang Chieh Chen, Chen Yu Wang, Kai Cheng Hsu, Wei Jan Huang

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine–derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aβ-aggregation as well as significantly disrupted Aβ-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aβ-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.

Original languageEnglish
Article number112193
Pages (from-to)112193
JournalEuropean Journal of Medicinal Chemistry
Volume192
DOIs
Publication statusPublished - Apr 15 2020

Keywords

  • Acetylcholine esterase
  • Acridine
  • Histone deacetylase
  • Multitarget

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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