title: Development of 2-thioxoquinazoline-4-one derivatives as dual and selective inhibitors of dynamin-related protein 1 (Drp1) and puromycin-sensitive aminopeptidase (PSA).
abstract: 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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Numadate
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mita
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy; D011485:Protein Binding; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: C000598354:3-(4-chloro-3-methoxyphenyl)-2-thioxoquinazoline-4-one; D004791:Enzyme Inhibitors; D052999:Quinazolinones; D011994:Recombinant Proteins; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; C486391:Dnm1l protein, mouse; D034281:Dynamins