Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy |
| |
| Institution: | 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;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. 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. 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, RangaReddy Dist, Hyderabad 500078, India;2. Department of Chemistry, Sri Krishnadevaraya University, Anantapur 515055, India |
| |
| Abstract: | Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC = 0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration. |
| |
| Keywords: | Tuberculosis DNA gyrase Thiazolopyridone ureas GyrB |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
