Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents
Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents
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DOI：
10.1021/ml300134b
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发表时间：
2012-09-01
影响因子：
4.2
通讯作者：
Ugarkar, Bheemarao G.
中科院分区：
文献类型：
--
作者：
Shirude, Pravin S.;Paul, Beena;Ugarkar, Bheemarao G.
NDH-2是结核分枝杆菌（Mycobacterium tuberculosis，Mtb）的一种必需呼吸酶，在Mtb的生理过程中起着重要作用。在此，我们提出了一个目标为基础的努力，以确定一个新的结构类的抑制剂NDH-2。对阿斯利康公司的高通量筛选导致喹啉基嘧啶类被鉴定为最有前途的NDH-2抑制剂。结构-活性关系研究表明，对NDH-2靶标的酶抑制（IC 50）有所改善，这反过来又转化为对Mtb的细胞活性。因此，这类化合物在酶抑制和细胞效能之间显示出良好的相关性。此外，最佳化合物的早期ADME分析显示出有希望的结果，并强调喹啉基嘧啶类是进一步开发的潜在先导。
NDH-2 is an essential respiratory enzyme in Mycobacterium tuberculosis (Mtb), which plays an important role in the physiology of Mtb. Herein, we present a target-based effort to identify a new structural class of inhibitors for NDH-2. High-throughput screening of the AstraZeneca corporate collection resulted in the identification of quinolinyl pyrimidines as the most promising class of NDH-2 inhibitors. Structure-activity relationship studies showed improved enzyme inhibition (IC50) against the NDH-2 target, which in turn translated into cellular activity against Mtb. Thus, the compounds in this class show a good correlation between enzyme inhibition and cellular potency. Furthermore, early ADME profiling of the best compounds showed promising results and highlighted the quinolinyl pyrimidine class as a potential lead for further development.