Optimization of a novel potent and selective bacterial DNA helicase inhibitor scaffold from a high throughput screening hit.
Optimization of a novel potent and selective bacterial DNA helicase inhibitor scaffold from a high throughput screening hit.
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从高通量筛选中优化新型有效且选择性的细菌 DNA 解旋酶抑制剂支架。
DOI：
10.1016/j.bmcl.2013.04.055
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发表时间：
2013
影响因子：
2.7
通讯作者：
Moir,DonaldT
中科院分区：
文献类型：
--
作者：
Li,Bing;Pai,Ramdas;Aiello,Daniel;Di,Ming;Barnes,MarjorieH;Peet,NortonP;Bowlin,TerryL;Moir,DonaldT
苯并双噻唑类化合物是一种新型的解旋酶抑制剂，通过对纯化的金黄色葡萄球菌（Sa）和炭疽芽孢杆菌（Ba）复制型解旋酶的高通量筛选得到。化学优化产生了具有纳摩尔效力的化合物59，其对抗两个B的DNA双链体链解旋活性。anthracis和S.金黄色解旋酶。59的选择性指数（SI= CC 50/IC 50）值大于500。动力学研究表明，基于苯并二噻唑的细菌解旋酶抑制剂与DNA底物竞争作用。因此，苯并双噻唑解旋酶抑制剂代表了一种有前途的新支架作为抗菌剂进行评估。
Benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) replicative helicases. Chemical optimization has produced compound 59 with nanomolar potency against the DNA duplex strand unwinding activities of both B. anthracis and S. aureus helicases. Selectivity index (SI=CC50/IC50) values for 59 were greater than 500. Kinetic studies demonstrated that the benzobisthiazole-based bacterial helicase inhibitors act competitively with the DNA substrate. Therefore, benzobisthiazole helicase inhibitors represent a promising new scaffold for evaluation as antibacterial agents.