Rudrapatna Controversy

Article pubs.acs.org/jmc Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B
Manoj G. Kale,† 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,‡ VK 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,‡
In the case of the benzimidazole ureas, the pocket occupied by the ribose of ATP was accessed by the pyridine ring attached to the benzimidazole
C-4 position.15b,c This interaction was considered important for the optimal binding of the ligand in the ATP-binding pocket of
GyrB. However, in the case of thiazolopyridine urea 3, similar access to the ribose pocket is not possible because of the

Figure 3. Docking of molecules into an homology model of the Mtb GyrB ATP-binding site. Hypothetical binding modes of ATP (yellow), benzimidazole urea 1a (cyan), and compound 3 (green). Important residues that participate in ligand interactions are Asp118, a conserved H2O molecule, Arg121, and Arg180. Access to the ribose binding region by 3 can be achieved from the thiazolopyridine C-5 position. Dotted green lines indicate HB interactions with the protein.
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dx.doi.org/10.1021/jm401268f | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

Article

Scheme 1. General Synthesis of Thiazolopyridine
Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

Article

Figure 4. (a) Hypothetical binding mode of ATP (orange, stick model) in the Mtb GyrB homology model23 (cyan) overlaid on the ATP-binding sites (5 Å) of Msm GyrB (orange, PDB code 4b6c17) and Spn ParE (magenta, PDB code 4mbc). The ligands from the 4b6c and 4mbc are removed for improved clarity. The ATP-binding sites of Mtb and Msm GyrB and Spn ParE are quite similar. (b) X-ray cocrystal structure showing key binding interactions of compounds 11 (green, PDB code 4mbc) and 20 (cyan, PDB code 4mb9) with selected Spn ParE ATP-binding-site residues. HB interactions between protein residues and associated water molecules are represented by gray dotted lines, whereas the green dotted lines represent the HB interactions made by the ligand with the protein and water molecule.

Optimization of Heterocycle at Site-2. On the basis of the binding-mode information, interactions of the heterocycle

Supporting Information for the docked pose of compound 25 in Spn ParE for a more detailed explanation).
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dx.doi.org/10.1021/jm401268f | J. Med. Chem. XXXX, XXX,