2. Academic Validation
  3. Lead optimization of 1,4-azaindoles as antimycobacterial agents

Lead optimization of 1,4-azaindoles as antimycobacterial agents

  • J Med Chem. 2014 Jul 10;57(13):5728-37. doi: 10.1021/jm500571f.
Pravin S Shirude 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, iMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
PMID: 24874895 DOI: 10.1021/jm500571f
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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