Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo.
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.
Department of Medicinal Chemistry, IMED Infection, AstraZeneca India , Bellary Road, Hebbal, Bangalore 560024, India.
Pravin S
PS
Shirude
Radha
R
Shandil
Claire
C
Sadler
Maruti
M
Naik
Vinayak
V
Hosagrahara
Shahul
S
Hameed
Vikas
V
Shinde
Chandramohan
C
Bathula
Vaishali
V
Humnabadkar
Naveen
N
Kumar
Jitendar
J
Reddy
Vijender
V
Panduga
Sreevalli
S
Sharma
Anisha
A
Ambady
Naina
N
Hegde
James
J
Whiteaker
Robert E
RE
McLaughlin
Humphrey
H
Gardner
Prashanti
P
Madhavapeddi
Vasanthi
V
Ramachandran
Parvinder
P
Kaur
Ashwini
A
Narayan
Supreeth
S
Guptha
Disha
D
Awasthy
Chandan
C
Narayan
Jyothi
J
Mahadevaswamy
K G
KG
Vishwas
Vijaykamal
V
Ahuja
Abhishek
A
Srivastava
K R
KR
Prabhakar
Sowmya
S
Bharath
Ramesh
R
Kale
Manjunatha
M
Ramaiah
Nilanjana Roy
NR
Choudhury
Vasan K
VK
Sambandamurthy
Suresh
S
Solapure
Pravin S
PS
Iyer
Shridhar
S
Narayanan
Monalisa
M
Chatterji
D000429:Alcohol Oxidoreductases; D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis