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Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA gyrase B

Kale, MG and Raichurkar, A and Shahul, HP and Waterson, D and McKinney, D and Manjunatha, MR and Kranthi, U and Koushik, K and Jena, LK and Shinde, V and Rudrapatna, S and Barde, S and Humnabadkar, V and Madhavapeddi, P and Basavarajappa, H and Ghosh, A and Ramya, V and Guptha, S and Sharma, S and Vachaspati, P and Kumar, KNM and Giridhar, J and Reddy, J and Panduga, V and Ganguly, S and Ahuja, V and Gaonkar, S and Kumar, CNN and Ogg, D and Tucker, JA and Boriack-Sjodin, PA and De Sousa, SM and Sambandamurthy, VK and Ghorpade, SR (2013) Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA gyrase B. Journal of Medicinal Chemistry. pp. 8834-8848.

Abstract

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 IC <sub>50</sub> < 1 nM and Mtb MIC < 0.1 muM 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. 2013 American Chemical Society

Item Type: Article
Additional Information: pubid: 235 nvp_institute: NIBR contributor_address: (Kale, Raichurkar, Shahul Hameed, Waterson, Manjunatha, Kranthi, Koushik, Jena, Shinde, Rudrapatna, Barde, Ghorpade) Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India (Humnabadkar, Madhavapeddi, Basavarajappa, Ghosh, Ramya, Guptha, Sharma, De Sousa, Sambandamurthy) Department of Biosciences, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India (Vachaspati, Kumar, Giridhar, Reddy, Panduga, Ganguly, Ahuja, Gaonkar, Kumar) DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India (McKinney) Chemistry, Infection IMed, AstraZeneca, Waltham, MA 02451, United States (Ogg, Tucker) Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield SK10 4TF, United Kingdom (Boriack-Sjodin) Biosciences, Infection IMed, AstraZeneca, Waltham, MA 02451, United States (Waterson) Medicines for Malaria Venture (MMV), Switzerland (Vachaspati) Novartis Institute for Tropical Diseases, Singapore (Kumar) Quintiles, Bangalore, India (Giridhar) C-CAMP, Bangalore, India (Gaonkar) Vipragen, Mysore, India (Tucker) Northern Institute of Cancer Research, University of Newcastle, Newcastle-upon-Tyne, United Kingdom (Boriack-Sjodin) Epizyme, Cambridge, MA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22042

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