Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities.
Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities.
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DOI：
10.1021/jm300922h
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发表时间：
2012-12-27
影响因子：
7.3
通讯作者：
Moir, Donald T.
中科院分区：
文献类型：
--
作者：
Li, Bing;Pai, Ramdas;Di, Ming;Aiello, Daniel;Barnes, Marjorie H.;Butler, Michelle M.;Tashjian, Tommy F.;Peet, Norton P.;Bowlin, Terry L.;Moir, Donald T.
耐药细菌感染的日益流行要求开发不受现有耐药机制制约的新的抗菌药。以前，我们描述了基于香豆素的未被开发的细菌靶标的抑制剂，即复制解旋酶。在这里，我们报告了优化的香豆素类抑制剂的合成和评价，它们对金黄色葡萄球菌(Sa)和炭疽杆菌(BA)解旋酶的效力提高了9-18倍。化合物20和22对炭疽杆菌和金黄色葡萄球菌螺旋酶的DNA双链解离活性的IC50值分别为3和1微米，且不影响单链DNA激活的ATPase活性。化合物20对金黄色葡萄球菌和炭疽杆菌的选择性指数(SI=CC50/MIC)分别为33和66，化合物22的选择性指数分别为20和40。此外，化合物20和22对多种环丙沙星耐药的MRSA菌株表现出较强的抗菌活性，其MIC值在0.5-4.2微克/毫升之间。
The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely, the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9–18-fold increased potency against S. aureus (Sa) and B. anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC50 values of 3 and 1 µM, respectively, against the DNA duplex strand-unwinding activities of both B. anthracis and S. aureus helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC50/MIC) values against S. aureus and B. anthracis for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains with MIC values ranging between 0.5–4.2 µg/mL.
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