Development of novel N-linked aminopiperidine-based mycobacterial DNA gyrase B inhibitors: Scaffold hopping from known antibacterial leads |
| |
| Institution: | 1. Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India;2. Dr Reddy''s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India;3. Zephase Therapeutics (an incubated company at the Dr Reddy''s Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India;1. Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey;2. Neuroscience Program, Graduate School of Health Sciences, Bahcesehir University, Istanbul, Turkey;3. College of Informatics, Huazhong Agricultural University (HZAU), Wuhan, China;4. Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, Pakistan;5. Department of Chemistry, University of Sargodha, Sargodha, Pakistan;1. Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States;2. Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany;3. Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK;1. Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, Hyderabad 500078, India;2. Department of Chemistry, Sri Krishnadevaraya University, Anantapur 515055, India;1. Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India;2. Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India;3. DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India;4. Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, UK;5. Biosciences, Infection iMed, AstraZeneca, Waltham, MA, USA |
| |
| 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. |
| |
| Keywords: | Tuberculosis DNA gyrase GyrB domain Aminopiperidine |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
