| Literature DB >> 24405701 |
Ramesh R Kale1, Manoj G Kale1, David Waterson1, Anandkumar Raichurkar1, Shahul P Hameed1, M R Manjunatha1, B K Kishore Reddy1, Krishnan Malolanarasimhan1, Vikas Shinde1, Krishna Koushik1, Lalit Kumar Jena1, Sreenivasaiah Menasinakai1, Vaishali Humnabadkar2, Prashanti Madhavapeddi2, Halesha Basavarajappa2, Sreevalli Sharma2, Radha Nandishaiah2, K N Mahesh Kumar3, Samit Ganguly3, Vijaykamal Ahuja3, Sheshagiri Gaonkar3, C N Naveen Kumar3, Derek Ogg4, P Ann Boriack-Sjodin5, Vasan K Sambandamurthy2, Sunita M de Sousa2, Sandeep R Ghorpade6.
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.Entities:
Keywords: DNA gyrase; GyrB; Thiazolopyridone ureas; Tuberculosis
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Year: 2013 PMID： 24405701 DOI： 10.1016/j.bmcl.2013.12.080
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823