1. Discovery of Pyrazolopyridones as a Novel Class of Noncovalent DprE1 Inhibitor with Potent Anti-Mycobacterial Activity
- Author
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Parvinder Kaur, Anisha Ambady, Sreevalli Sharma, Vinayak Hosagrahara, Ashwini Narayan, Vasanthi Ramachandran, Suresh Rudrapatna, Supreeth Guptha, Pravin S. Shirude, Vasan K. Sambandamurthy, Jyothi Mahadevaswamy, Ramachandran Sreekanth A, Kavitha Nagalapur, Anandkumar Raichurkar, Naina Hegde, Manoranjan Panda, and Vaishali Humnabadkar
- Subjects
Pyridones ,medicine.drug_class ,Antitubercular Agents ,Microbial Sensitivity Tests ,Pharmacology ,Antimycobacterial ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,Minimum inhibitory concentration ,Bacterial Proteins ,Catalytic Domain ,Drug Resistance, Bacterial ,Drug Discovery ,medicine ,Gene ,biology ,Chemistry ,Active site ,biology.organism_classification ,Resistance mutation ,In vitro ,Molecular Docking Simulation ,Alcohol Oxidoreductases ,Biochemistry ,Docking (molecular) ,Mutation ,biology.protein ,Pyrazoles ,Molecular Medicine ,Oxidoreductases - 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.
- Published
- 2014
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