1. Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy
- Author
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P. Ann Boriack-Sjodin, B. K. Kishore Reddy, Ramesh R. Kale, Vijaykamal Ahuja, Sunita M. de Sousa, Krishnan Malolanarasimhan, Sheshagiri Gaonkar, Anandkumar Raichurkar, Sreenivasaiah Menasinakai, Halesha D. Basavarajappa, Prashanti Madhavapeddi, M. R. Manjunatha, Shahul Hameed, David Waterson, Radha Nandishaiah, Vasan K. Sambandamurthy, C. N. Naveen Kumar, Derek Ogg, Vikas Shinde, Vaishali Humnabadkar, Krishna Koushik, Sreevalli Sharma, K. N. Mahesh Kumar, Sandeep R. Ghorpade, Kale Manoj Ganpat, Samit Ganguly, and Lalit kumar Jena
- Subjects
Pyridones ,Stereochemistry ,Clinical Biochemistry ,Antitubercular Agents ,Administration, Oral ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Biochemistry ,DNA gyrase ,Hydrophobic effect ,Mycobacterium tuberculosis ,Inhibitory Concentration 50 ,Mice ,chemistry.chemical_compound ,Drug Discovery ,Ribose ,Animals ,Topoisomerase II Inhibitors ,Urea ,Molecular Biology ,IC50 ,chemistry.chemical_classification ,Molecular Structure ,biology ,Organic Chemistry ,Active site ,biology.organism_classification ,Disease Models, Animal ,Thiazoles ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,DNA - 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.
- Published
- 2014