Development of novel N-linked aminopiperidine-based mycobacterial DNA gyrase B inhibitors: Scaffold hopping from known antibacterial leads
- Authors
- Jeankumar, V.U., Renuka, J., Pulla, V.K., Soni, V., Sridevi, J.P., Suryadevara, P., Shravan, M., Medishetti, R., Kulkarni, P., Yogeeswari, P., and Sriram, D.
- ID
- ZDB-PUB-140318-24
- Date
- 2014
- Source
- International Journal of Antimicrobial Agents 43(3): 269-78 (Journal)
- Registered Authors
- Kulkarni, Pushkar
- Keywords
- Aminopiperidine, DNA gyrase, GyrB domain, Tuberculosis
- MeSH Terms
-
- Amines/adverse effects
- Amines/chemistry
- Amines/isolation & purification
- Amines/pharmacology*
- Animals
- Antitubercular Agents/adverse effects
- Antitubercular Agents/isolation & purification
- Antitubercular Agents/pharmacology*
- Bacterial Proteins/antagonists & inhibitors*
- DNA Gyrase/metabolism*
- Enzyme Inhibitors/adverse effects
- Enzyme Inhibitors/isolation & purification
- Enzyme Inhibitors/pharmacology*
- Humans
- Inhibitory Concentration 50
- Microbial Sensitivity Tests
- Models, Molecular
- Molecular Docking Simulation
- Molecular Structure
- Mycobacterium/enzymology*
- Piperidines/chemistry
- Piperidines/isolation & purification
- Piperidines/pharmacology*
- Zebrafish
- PubMed
- 24434114 Full text @ Int. J. Antimicrob. Agents
DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase that ensures the regulation of DNA topology and has been genetically demonstrated to be a bactericidal drug target. We present the discovery and optimisation of a novel series of mycobacterial DNA gyrase inhibitors with a high degree of specificity towards the mycobacterial ATPase domain. Compound 5-fluoro-1-(2-(4-(4-(trifluoromethyl)benzylamino)piperidin-1-yl)ethyl)indoline-2,3-dione (17) emerged as the most potent lead, exhibiting inhibition of MTB DNA gyrase supercoiling assay with an IC50 (50% inhibitory concentration) of 3.6 ± 0.16 μM, a Mycobacterium smegmatis GyrB IC50 of 10.6 ± 0.6 μM, and MTB minimum inhibitory concentrations of 6.95 μM and 10 μM against drug-sensitive (MTB H37Rv) and extensively drug-resistant strains, respectively. Furthermore, the compounds did not show any signs of cardiotoxicity in zebrafish ether-à-go-go-related gene (zERG), and hence constitute a major breakthrough among the otherwise cardiotoxic N-linked aminopiperidine analogues.