Thiazolopyridine Ureas asNovel Antitubercular AgentsActing through Inhibition of DNA Gyrase B.
- Resource Type
- Article
- Authors
- Kale, Manoj G.; Raichurkar, Anandkumar; P., Shahul Hameed; Waterson, David; McKinney, David; Manjunatha, M. R.; Kranthi, Usha; Koushik, Krishna; Jena, Lalit kumar; Shinde, Vikas; Rudrapatna, Suresh; Barde, Shubhada; Humnabadkar, Vaishali; Madhavapeddi, Prashanti; Basavarajappa, Halesha; Ghosh, Anirban; Ramya, VK; Guptha, Supreeth; Sharma, Sreevalli; Vachaspati, Prakash
- Source
- Journal of Medicinal Chemistry. Vol. 56 Issue 21, p8834-8848. 15p.
- Subject
- *THIAZOLES
*PYRIDINE
*DNA topoisomerase II
*ANTITUBERCULAR agents
*SCAFFOLD proteins
*MYCOBACTERIUM tuberculosis
*UREA
- Language
- ISSN
- 0022-2623
A pharmacophore-based search ledto the identification of thiazolopyridineureas as a novel scaffold with antitubercular activity acting throughinhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the bindingmode of thiazolopyridines in a Mycobacterium tuberculosis(Mtb) GyrB homology model prompted exploration of the side chainsat the thiazolopyridine ring C-5 position to access the ribose/solventpocket. Potent compounds with GyrB IC50⤠1 nM andMtb MIC ⤠0.1 μM were obtained with certain combinationsof side chains at the C-5 position and heterocycles at the C-6 positionof the thiazolopyridine core. Substitutions at C-5 also enabled optimizationof the physicochemical properties. Representative compounds were cocrystallizedwith Streptococcus pneumoniae(Spn)ParE; these confirmed the binding modes predicted by the homologymodel. The target link to GyrB was confirmed by genetic mapping ofthe mutations conferring resistance to thiazolopyridine ureas. Thecompounds are bactericidal in vitro and efficacious in vivo in anacute murine model of tuberculosis. [ABSTRACT FROM AUTHOR]