Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA)
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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DOI：
10.1248/cpb.c14-00333
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发表时间：
2014-10-01
影响因子：
1.7
通讯作者：
Hashimoto, Yuichi
中科院分区：
文献类型：
--
作者：
Numadate, Akiyoshi;Mita, Yusuke;Hashimoto, Yuichi
一种已建立的动力蛋白相关蛋白1 （Drpl）抑制剂3-（2,4-二氯-5-甲氧基苯基）-2-硫氧喹啉-4- 1 （mdii -1）最近也被报道显示出有效的嘌呤霉素敏感氨基肽酶（PSA）抑制活性。在此，我们报道了mdivi-1衍生物的结构发展和合成化合物的构效关系（SAR）分析，以及结构相关的psa特异性抑制剂3-(2,6-二乙基苯基喹啉-2,4-二酮（PAQ-22），目的是确定抑制活性的关键结构特征，以开发Drpl的选择性抑制剂，这是治疗亨廷顿病的潜在靶点。在合成的化合物中，3-(4-氯-甲氧基苯基1)-2-硫代喹唑啉-4- 1 （10g）对Drpl的抑制活性比mdivi-1更强，对PSA具有较高的选择性。
An established inhibitor of dynamin-related protein 1 (Drpl), 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-diethylphenyOquinazoline-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-chloro3-methoxypheny1)-2-thioxoquinazoline-4-one (10g) exhibited more potent Drp1-inhibitory activity than mdivi-1 with high selectivity for Drpl over PSA.