| Literature DB >> 24088190 |
Manoj G Kale1, Anandkumar Raichurkar, Shahul Hameed P, David Waterson, David McKinney, M R Manjunatha, Usha Kranthi, Krishna Koushik, Lalit kumar Jena, Vikas Shinde, Suresh Rudrapatna, Shubhada Barde, Vaishali Humnabadkar, Prashanti Madhavapeddi, Halesha Basavarajappa, Anirban Ghosh, V K Ramya, Supreeth Guptha, Sreevalli Sharma, Prakash Vachaspati, K N Mahesh Kumar, Jayashree Giridhar, Jitendar Reddy, Vijender Panduga, Samit Ganguly, Vijaykamal Ahuja, Sheshagiri Gaonkar, C N Naveen Kumar, Derek Ogg, Julie A Tucker, P Ann Boriack-Sjodin, Sunita M de Sousa, Vasan K Sambandamurthy, Sandeep R Ghorpade.
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 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.Entities:
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Year: 2013 PMID： 24088190 DOI： 10.1021/jm401268f
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446