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Lookup NU author(s): Dr Julie Tucker
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A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.
Author(s): Kale MG, Raichurkar A, Hameed S, Waterson D, McKinney D, Manjunatha MR, Kranthi U, Koushik K, Jena L, Shinde V, Rudrapatana S, Humnabadkar V, Madhavapeddi P, Basavarajappa H, Ghosh A, Ramya VK, Guptha S, Sharma S, Vachaspathi P, Kumar KNM, Giridhar J, Reddy J, Panduga V, Ganguly S, Ahuja V, Gaonkar S, Kumar CNN, Ogg D, Tucker J, Boriack-Sjodin A, DeSousa SM, Sambandamurthy VK, Ghorpade SR
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 2013
Volume: 56
Issue: 21
Pages: 8834-8848
Print publication date: 03/10/2013
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
URL: http://dx.doi.org/10.1021/jm401268f
DOI: 10.1021/jm401268f
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