Development of novel N-linked aminopiperidine-based mycobacterial DNA gyrase B inhibitors: scaffold hopping from known antibacterial leads.

Abstract

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.

• Authors: Variam Ullas Jeankumar, Janupally Renuka, Venkat Koushik Pulla, Vijay Soni, Jonnalagadda Padma Sridevi, Priyanka Suryadevara, Morla Shravan, Raghavender Medishetti, Pushkar Kulkarni, Perumal Yogeeswari, Dharmarajan Sriram
• Journal: International journal of antimicrobial agents (Int J Antimicrob Agents) Vol. 43 Issue 3 Pg. 269-78 (Mar 2014) ISSN: 1872-7913 [Electronic] Netherlands
• PMID: 24434114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Chemical References

• Amines
• Antitubercular Agents
• Bacterial Proteins
• Enzyme Inhibitors
• Piperidines
• DNA Gyrase

Topics

• Amines (adverse effects, chemistry, isolation & purification, pharmacology)
• Animals
• Antitubercular Agents (adverse effects, isolation & purification, pharmacology)
• Bacterial Proteins (antagonists & inhibitors)
• DNA Gyrase (metabolism)
• Enzyme Inhibitors (adverse effects, isolation & purification, pharmacology)
• Humans
• Inhibitory Concentration 50
• Microbial Sensitivity Tests
• Models, Molecular
• Molecular Docking Simulation
• Molecular Structure
• Mycobacterium (enzymology)
• Piperidines (chemistry, isolation & purification, pharmacology)
• Zebrafish