Development of 2-thioxoquinazoline-4-one derivatives as dual and selective inhibitors of dynamin-related protein 1 (Drp1) and puromycin-sensitive aminopeptidase (PSA)

Akiyoshi Numadate, Yusuke Mita, Yotaro Matsumoto, Shinya Fujii, Yuichi Hashimoto

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

An established inhibitor ot dynamin-related protein 1 (Drp1), 3-(2,4-dichloro-5-methoxyphenyl)- 2- thioxoquinazoline-4-one (mdivi-1), was recently reported also to show potent puromycin-sensitive aminopeptidase (PSA)-inhibitory activity. Herein, we report structural development of mdivi-1 derivatives and structure-activity relationship (SAR) analysis of the synthesized compounds, as well as the structurally related PSA-specific inhibitor 3-(2,6-diethylphenyl)quinazoline-2,4-dione (PAQ-22), with the aim of identifying key structural features for inhibitory activity in order to develop selective inhibitors of Drpl, which is a potential target for treatment of Huntington's disease. Among the synthesized compounds, 3-(4-chloro3methoxyphenyl)-2-thioxoquinazoline-4-one 10g) exhibited more potent Drpl-inhibitory activity than mdivi-1 with high selectivity for Drpl over PSA.

Original languageEnglish
Pages (from-to)979-988
Number of pages10
JournalChemical and Pharmaceutical Bulletin
Volume62
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1
Externally publishedYes

Keywords

  • 2-thioxoquinazoline-4-one
  • Drpl puromycin-sensitive aminopeptidase
  • Dynamin-related protein 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Drug Discovery

Fingerprint Dive into the research topics of 'Development of 2-thioxoquinazoline-4-one derivatives as dual and selective inhibitors of dynamin-related protein 1 (Drp1) and puromycin-sensitive aminopeptidase (PSA)'. Together they form a unique fingerprint.

Cite this