Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position

Thuy Nguyen, Yuji Sakasegawa, Katsumi Doh-Ura, Mei Lin Go

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP121-231) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP121-231.

Original languageEnglish
Pages (from-to)2917-2929
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number7
DOIs
Publication statusPublished - 2011 Jul 1

Keywords

  • Binding to human prion protein fragment
  • Cell-based anti-prion activity
  • Drug-like properties
  • PAMPA-BBB permeability
  • Pgp substrate
  • Quinacrine analogs

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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