Department of Medicinal Chemistry, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
J Med Chem. 2014 Aug 14;57(15):6572-82. doi: 10.1021/jm500833f. Epub 2014 Jul 16.
Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE)>0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.
二芳基噻唑（DAT）是从多样性筛选中获得的一个命中化合物，对结核分枝杆菌（Mtb）具有很强的抗分枝杆菌活性。在系统的药物化学探索中，我们证明了优化效力和理化性质的化学机会。这项工作产生了 10 多个具有亚微摩尔 MIC 和理想理化性质的化合物。该系列化合物具有很强的抗分枝杆菌活性，分子量低，成为一个有吸引力的先导物（抗菌配体效率（ALE）>0.4）。该系列化合物表现出优异的杀菌活性，对敏感和耐药的结核分枝杆菌均有效。突变分析表明，prrB 的突变赋予了 DAT 化合物的耐药性，但对测试的参考药物没有耐药性。感应激酶 PrrB 属于 PrrBA 双组分系统，可能是 DAT 的靶标。PrrBA 是结核分枝杆菌中保守的、必需的调节机制，已被证明在毒力和代谢适应应激方面发挥作用。因此，DAT 为理解抗分枝杆菌药物发现的全新靶标系统提供了机会。
