Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy

Autor:	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, Lalit kumar Jena
Rok vydání:	2014
Předmět:	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
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 24:870-879
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2013.12.080
Popis:	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.
Databáze:	OpenAIRE
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