Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines
Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines
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DOI：
10.1016/j.bmcl.2011.07.059
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发表时间：
2011-09-15
影响因子：
2.7
通讯作者：
Finn, John
中科院分区：
文献类型：
--
作者：
Li, Xiaoming;Hilgers, Mark;Finn, John
二氢叶酸还原酶(DHFR)抑制剂，如甲氧苄啶(TMP)，长期以来在细菌感染的治疗中发挥着重要作用。毫不奇怪，经过几十年的使用，现在细菌对TMP产生了抗药性，因此需要开发包括这些抗药性菌株在内的具有更广泛光谱的新型抗菌剂。在这项研究中，我们对2，4-二氨基喹唑类化合物的抗菌效力和选择性进行了优化。利用基于结构的药物设计，发现了几种7-芳基-2，4-二氨基喹唑类化合物，它们对细菌DHFR具有良好的亚100皮摩尔效力。这些化合物具有良好的抗菌活性，特别是对革兰氏阳性病原菌，包括TMP耐药菌株。(C)2011爱思唯尔有限公司。保留所有权利。
Dihydrofolate reductase (DHFR) inhibitors such as trimethoprim(TMP) have long played a significant role in the treatment of bacterial infections. Not surprisingly, after decades of use there is now bacterial resistance to TMP and therefore a need to develop novel antibacterial agents with expanded spectrum including these resistant strains. In this study, we investigated the optimization of 2,4-diamnoquinazolines for antibacterial potency and selectivity. Using structure-based drug design, several 7-aryl-2,4-diaminoquinazolines were discovered that have excellent sub-100 picomolar potency against bacterial DHFR. These compounds have good antibacterial activity especially on gram-positive pathogens including TMP-resistant strains. (C) 2011 Elsevier Ltd. All rights reserved.