Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents
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- 作者：Pravin S. Shirude ; Radha K. Shandil ; M. R. Manjunatha ; Claire Sadler ; Manoranjan Panda ; Vijender Panduga ; Jitendar Reddy ; Ramanatha Saralaya ; Robert Nanduri ; Anisha Ambady ; Sudha Ravishankar ; Vasan K. Sambandamurthy ; Vaishali Humnabadkar ; Lalit K. Jena ; Rudrapatna S. Suresh ; Abhishek Srivastava ; K. R. Prabhakar ; James Whiteaker ; Robert E. McLaughlin ; Sreevalli Sharma ; Christopher B. Cooper ; Khisi Mdluli ; Scott Butler ; Pravin S. Iyer ; Shridhar Narayanan ; Monalisa Chatterji
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：July 10, 2014
- 年：2014
- 卷：57
- 期：13
- 页码：5728-5737
- 全文大小：460K
- ISSN：1520-4804
文摘
In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-尾-d-ribose-2鈥?epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.