title: Lead optimization of 1,4-azaindoles as antimycobacterial agents.
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.
authors.affiliation: Department of Medicinal Chemistry, iMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Shirude
authors.forename: Radha K
authors.initials: RK
authors.lastname: Shandil
authors.forename: M R
authors.initials: MR
authors.lastname: Manjunatha
authors.forename: Claire
authors.initials: C
authors.lastname: Sadler
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.forename: Robert
authors.initials: R
authors.lastname: Nanduri
authors.forename: Anisha
authors.initials: A
authors.lastname: Ambady
authors.forename: Sudha
authors.initials: S
authors.lastname: Ravishankar
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.forename: Lalit K
authors.initials: LK
authors.lastname: Jena
authors.forename: Rudrapatna S
authors.initials: RS
authors.lastname: Suresh
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.forename: K R
authors.initials: KR
authors.lastname: Prabhakar
authors.forename: James
authors.initials: J
authors.lastname: Whiteaker
authors.forename: Robert E
authors.initials: RE
authors.lastname: McLaughlin
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cooper
authors.forename: Khisi
authors.initials: K
authors.lastname: Mdluli
authors.forename: Scott
authors.initials: S
authors.lastname: Butler
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Iyer
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.forename: Monalisa
authors.initials: M
authors.lastname: Chatterji
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C522780:4-azaindole; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007211:Indoles; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6