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

• Published in: International journal of antimicrobial agents 2014-03, Vol.43 (3), p.269-278
• Main Authors: Jeankumar, Variam Ullas, Renuka, Janupally, Pulla, Venkat Koushik, Soni, Vijay, Sridevi, Jonnalagadda Padma, Suryadevara, Priyanka, Shravan, Morla, Medishetti, Raghavender, Kulkarni, Pushkar, Yogeeswari, Perumal, Sriram, Dharmarajan
• Format: Article
• Language: English
• Subjects: Amines - adverse effects; Amines - chemistry; Amines - isolation & purification; Amines - pharmacology; Aminopiperidine; Animals; Antitubercular Agents - adverse effects; Antitubercular Agents - isolation & purification; Antitubercular Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; DNA gyrase; DNA Gyrase - metabolism; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; GyrB domain; Humans; Infectious Disease; Inhibitory Concentration 50; Microbial Sensitivity Tests; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Mycobacterium - enzymology; Piperidines - chemistry; Piperidines - isolation & purification; Piperidines - pharmacology; Tuberculosis; Zebrafish
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2013.12.006

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.