- Lead optimization of 1,4-azaindoles as antimycobacterial agents.
Lead optimization of 1,4-azaindoles as antimycobacterial agents.
Journal of medicinal chemistry (2014-05-31)
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
PMID24874895
ABSTRACT
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.
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(Hydroxypropyl)methyl cellulose, viscosity 2,600-5,600 cP, 2 % in H2O(20 °C)(lit.)