American Chemical Society
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Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents

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journal contribution
posted on 2014-07-10, 00:00 authored by 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
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-β-d-ribose-2′-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.