- Lead optimization of 1,4-azaindoles as antimycobacterial agents
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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.
- Shirude, Pravin S.,Shandil, Radha K.,Manjunatha,Sadler, Claire,Panda, Manoranjan,Panduga, Vijender,Reddy, Jitendar,Saralaya, Ramanatha,Nanduri, Robert,Ambady, Anisha,Ravishankar, Sudha,Sambandamurthy, Vasan K.,Humnabadkar, Vaishali,Jena, Lalit K.,Suresh, Rudrapatna S.,Srivastava, Abhishek,Prabhakar,Whiteaker, James,McLaughlin, Robert E.,Sharma, Sreevalli,Cooper, Christopher B.,Mdluli, Khisi,Butler, Scott,Iyer, Pravin S.,Narayanan, Shridhar,Chatterji, Monalisa
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p. 5728 - 5737
(2014/08/05)
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- Azaindoles: Noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo
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We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-D-ribose2′-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.
- Shirude, Pravin S.,Shandil, Radha,Sadler, Claire,Naik, Maruti,Hosagrahara, Vinayak,Hameed, Shahul,Shinde, Vikas,Bathula, Chandramohan,Humnabadkar, Vaishali,Kumar, Naveen,Reddy, Jitendar,Panduga, Vijender,Sharma, Sreevalli,Ambady, Anisha,Hegde, Naina,Whiteaker, James,McLaughlin, Robert E.,Gardner, Humphrey,Madhavapeddi, Prashanti,Ramachandran, Vasanthi,Kaur, Parvinder,Narayan, Ashwini,Guptha, Supreeth,Awasthy, Disha,Narayan, Chandan,Mahadevaswamy, Jyothi,Vishwas,Ahuja, Vijaykamal,Srivastava, Abhishek,Prabhakar, Kr,Bharath, Sowmya,Kale, Ramesh,Ramaiah, Manjunatha,Choudhury, Nilanjana Roy,Sambandamurthy, Vasan K.,Solapure, Suresh,Iyer, Pravin S.,Narayanan, Shridhar,Chatterji, Monalisa
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supporting information
p. 9701 - 9708
(2014/01/06)
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