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J Med Chem. 2014 Jul 10;57(13):5728-37. doi: 10.1021/jm500571f. Epub 2014 Jun 20.

Lead optimization of 1,4-azaindoles as antimycobacterial agents.

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Department of Medicinal Chemistry, iMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.


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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