Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10594853 | Bioorganic & Medicinal Chemistry Letters | 2014 | 10 Pages |
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
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Ramesh R. Kale, Manoj G. Kale, David Waterson, Anandkumar Raichurkar, Shahul P. Hameed, M.R. Manjunatha, B.K. Kishore Reddy, Krishnan Malolanarasimhan, Vikas Shinde, Krishna Koushik, Lalit Kumar Jena, Sreenivasaiah Menasinakai, Vaishali Humnabadkar,