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  • Title: Development of novel N-linked aminopiperidine-based mycobacterial DNA gyrase B inhibitors: scaffold hopping from known antibacterial leads.
    Author: Jeankumar VU, Renuka J, Pulla VK, Soni V, Sridevi JP, Suryadevara P, Shravan M, Medishetti R, Kulkarni P, Yogeeswari P, Sriram D.
    Journal: Int J Antimicrob Agents; 2014 Mar; 43(3):269-78. PubMed ID: 24434114.
    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.
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