Antiprion activity of functionalized 9-aminoacridines related to quinacrine

Hanh Thuy Nguyen Thi, Chong Yew Lee, Kenta Teruya, Wei Yi Ong, Katsumi Doh-ura, Mei Lin Go

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

A library of functionalized 6-chloro-2-methoxy-(N9-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC50 values (0.1-0.7 μM) on all cell models, was able to clear PrPSc at non-toxic concentrations of 1.2-2.5 μM, and was more active than quinacrine in terms of EC50 values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.

Original languageEnglish
Pages (from-to)6737-6746
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number14
DOIs
Publication statusPublished - 2008 Jul 15

Keywords

  • 6-Chloro-2-methoxy-(N-substituted)acridin-9-amines
  • Antiprion activity
  • Murine neuroblastoma cells infected with scrapie prion strains
  • Quinacrine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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