Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA)

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  • Numadate Akiyoshi
    Institute of Molecular and Cellular Biosciences, The University of Tokyo
  • Mita Yusuke
    Institute of Molecular and Cellular Biosciences, The University of Tokyo
  • Matsumoto Yotaro
    Faculty of Pharma Sciences, Teikyo University
  • Fujii Shinya
    Institute of Molecular and Cellular Biosciences, The University of Tokyo
  • Hashimoto Yuichi
    Institute of Molecular and Cellular Biosciences, The University of Tokyo

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An established inhibitor of 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 Drp1, which is a potential target for treatment of Huntington’s disease. Among the synthesized compounds, 3-(4-chloro-3-methoxyphenyl)-2-thioxoquinazoline-4-one (10g) exhibited more potent Drp1-inhibitory activity than mdivi-1 with high selectivity for Drp1 over PSA.

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