- 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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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.
- Numadate, Akiyoshi,Mita, Yusuke,Matsumoto, Yotaro,Fujii, Shinya,Hashimoto, Yuichi
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p. 979 - 988
(2015/02/19)
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- Specific inhibitors of puromycin-sensitive aminopeptidase with a 3-(halogenated phenyl)-2,4(1H,3H)-quinazolinedione skeleton
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Specific puromycin-sensitive aminopeptidase (PSA) inhibitors with a 3-(halogenated phenyl)-2,4(1H,3H)-quinazolinedione skeleton were prepared and their structure-activity relationships were investigated. The nature (F, Cl or Br), number and position(s) of the halogen atom(s) introduced into the 3-phenyl group were concluded to be critical determinants of the inhibitory activity.
- Matsumoto, Yotaro,Noguchi-Yachide, Tomomi,Nakamura, Masaharu,Mita, Yusuke,Numadate, Akiyoshi,Hashimoto, Yuichi
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p. 1449 - 1463
(2013/08/23)
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