Structure aided design of chimeric antibiotics
Structure aided design of chimeric antibiotics
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DOI：
10.1016/j.bmcl.2012.02.019
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发表时间：
2012-04-01
影响因子：
2.7
通讯作者：
Cooper, Matthew A.
中科院分区：
文献类型：
--
作者：
Karoli, Tomislav;Mamidyala, Sreeman K.;Cooper, Matthew A.
抗生素耐药性的上升引起了临床的极大关注。减少耐药性发展的一种方法是联合使用两种或两种以上不同作用模式的抗生素。然而，很难控制两种药物的分布和药代动力学，以确保这两种药物的浓度都保持在治疗效果的范围内，同时避免不良反应。人们已经探索了两种药物通过柔性连接物连接在一起的混合药物，但得到的大而灵活的分子生物利用度很低。我们已经开发了一种使用点击化学的嵌合方法，在这种方法中，两种药物的药效团重叠成一个更小、更像药物的分子。通过电子结构对接辅助化合物的设计和选择。我们制备了一系列化合物，其中包括对甲氧苄氨嘧啶、二氢叶酸还原酶、环丙沙星、DNA旋转酶和拓扑异构酶IV都有活性的候选化合物。所得到的含有三氮唑的分子对药物敏感和耐药的革兰氏阴性和革兰氏阳性细菌显示出适度但广泛的活性，没有观察到的细胞毒性。(C)2012爱思唯尔有限公司。保留所有权利。
The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and pharmacokinetics of two drugs to ensure both concentrations remain within the range of therapeutic efficacy whilst avoiding adverse effects. Hybrid drugs, where two drugs are linked together with a flexible linker, have been explored, but the resultant large, flexible molecules can have poor bioavailability. We have developed a chimeric approach using click chemistry where the pharmacophores of two drugs are overlapped into a single smaller, more drug-like molecule. Design and selection of compounds were assisted by in silico structural docking. We prepared a series of compounds that include candidates showing activity against the targets of both trimethoprim; dihydrofolate reductase, and ciprofloxacin; DNA gyrase and topoisomerase IV. The resultant triazole containing molecules show modest, but broad spectrum activities against drug sensitive and resistant Gram-negative and Gram-positive bacteria, with no observable cytotoxicity. (C) 2012 Elsevier Ltd. All rights reserved.