Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents
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- 作者：Pravin S. Shirude ; Beena Paul ; Nilanjana Roy Choudhury ; Chaitanya Kedari ; Balachandra Bandodkar ; Bheemarao G. Ugarkar
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：3
- 期：9
- 页码：736-740
- 全文大小：290K
- 年卷期：v.3,no.9(September 13, 2012)
- ISSN：1948-5875
文摘
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鈥揳ctivity 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.