Department of Medicinal Chemistry, ‡Department of Biosciences, and §DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
J Med Chem. 2013 Nov 14;56(21):8834-48. doi: 10.1021/jm401268f. Epub 2013 Oct 18.
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.
基于药效团的搜索发现噻唑并嘧啶脲是一种新型的具有抗结核活性的支架，通过抑制 DNA 回旋酶 B（GyrB）ATP 酶发挥作用。噻唑并嘧啶类化合物在结核分枝杆菌（Mtb）GyrB 同源模型中的结合模式评估促使我们探索噻唑并嘧啶环 C-5 位置的侧链，以进入核糖/溶剂口袋。通过噻唑并嘧啶核心 C-5 位置的侧链和 C-6 位置的杂环的某些组合，获得了 GyrB IC50≤1 nM 和 Mtb MIC≤0.1 μM 的具有强大抑制活性的化合物。C-5 取代还能够优化理化性质。代表性化合物与肺炎链球菌（Spn）ParE 共结晶；这些证实了同源模型预测的结合模式。通过对赋予噻唑并嘧啶脲类化合物抗性的突变进行遗传定位，确认了靶标与 GyrB 的连接。这些化合物在体外具有杀菌作用，在急性结核小鼠模型中具有疗效。
