title: Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity.
abstract: A novel pyrazolopyridone class of inhibitors was identified from whole cell screening against Mycobacterium tuberculosis (Mtb). The series exhibits excellent bactericidality in vitro, resulting in a 4 log reduction in colony forming units following compound exposure. The significant modulation of minimum inhibitory concentration (MIC) against a Mtb strain overexpressing the Rv3790 gene suggested the target of pyrazolopyridones to be decaprenylphosphoryl-β-D-ribose-2'-epimerase (DprE1). Genetic mapping of resistance mutation coupled with potent enzyme inhibition activity confirmed the molecular target. Detailed biochemical characterization revealed the series to be a noncovalent inhibitor of DprE1. Docking studies at the active site suggest that the series can be further diversified to improve the physicochemical properties without compromising the antimycobacterial activity. The pyrazolopyridone class of inhibitors offers an attractive non-nitro lead series targeting the essential and vulnerable DprE1 enzyme for the discovery of novel antimycobacterial agents to treat both drug susceptible and drug resistant strains of Mtb.
authors.affiliation: Department of Chemistry, ‡Department of Bioscience, IMED Infection, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Shirude
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.forename: Kavitha
authors.initials: K
authors.lastname: Nagalapur
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: Parvinder
authors.initials: P
authors.lastname: Kaur
authors.forename: Supreeth
authors.initials: S
authors.lastname: Guptha
authors.forename: Ashwini
authors.initials: A
authors.lastname: Narayan
authors.forename: Jyothi
authors.initials: J
authors.lastname: Mahadevaswamy
authors.forename: Anisha
authors.initials: A
authors.lastname: Ambady
authors.forename: Naina
authors.initials: N
authors.lastname: Hegde
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Rudrapatna
authors.forename: Vinayak P
authors.initials: VP
authors.lastname: Hosagrahara
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
mesh_terms: D000429:Alcohol Oxidoreductases; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D020134:Catalytic Domain; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011720:Pyrazoles; D011728:Pyridones; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis