新型 4-苯胺基喹啉和 4-苯胺基喹唑啉的抗结核活性。
Anti-tubercular activity of novel 4-anilinoquinolines and 4-anilinoquinazolines.
机构信息
Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Seattle Children's Research Institute, Seattle, WA 98109, USA.
出版信息
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2695-2699. doi: 10.1016/j.bmcl.2019.07.012. Epub 2019 Jul 10.
Abstract
We screened a series of 4-anilinoquinolines and 4-anilinoquinazolines and identified novel inhibitors of Mycobacterium tuberculosis (Mtb). The focused 4-anilinoquinoline/quinazoline scaffold arrays yielded compounds with high potency and the identification of 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (34) with an MIC value of 0.63-1.25 µM. We also defined a series of key structural features, including the benzyloxy aniline and the 6,7-dimethoxy quinoline ring, that are important for Mtb inhibition. Importantly the compounds showed very limited toxicity and scope for further improvement by iterative medicinal chemistry.
摘要
我们筛选了一系列 4-苯胺基喹啉和 4-苯胺基喹唑啉，鉴定出了新型结核分枝杆菌（Mycobacterium tuberculosis，Mtb）抑制剂。聚焦的 4-苯胺基喹啉/喹唑啉支架阵列产生了具有高活性的化合物，并鉴定出了 6,7-二甲氧基-N-(4-((4-甲基苄基)氧基)苯基)喹啉-4-胺（34），其 MIC 值为 0.63-1.25 µM。我们还确定了一系列关键的结构特征，包括苄氧基苯胺和 6,7-二甲氧基喹啉环，这些特征对于 Mtb 抑制很重要。重要的是，这些化合物的毒性非常有限，通过迭代药物化学有进一步改善的空间。
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