噻唑并吡啶脲类化合物作为DNA促旋酶B抑制剂：抗结核活性和疗效的优化
Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy.
作者信息
Kale Ramesh R, Kale Manoj G, Waterson David, Raichurkar Anandkumar, Hameed Shahul P, Manjunatha M R, Kishore Reddy B K, Malolanarasimhan Krishnan, Shinde Vikas, Koushik Krishna, Jena Lalit Kumar, Menasinakai Sreenivasaiah, Humnabadkar Vaishali, Madhavapeddi Prashanti, Basavarajappa Halesha, Sharma Sreevalli, Nandishaiah Radha, Mahesh Kumar K N, Ganguly Samit, Ahuja Vijaykamal, Gaonkar Sheshagiri, Naveen Kumar C N, Ogg Derek, Boriack-Sjodin P Ann, Sambandamurthy Vasan K, de Sousa Sunita M, Ghorpade Sandeep R
机构信息
Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
出版信息
Bioorg Med Chem Lett. 2014 Feb 1;24(3):870-9. doi: 10.1016/j.bmcl.2013.12.080. Epub 2013 Dec 25.
Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.
从噻唑并吡啶脲类进行骨架跃迁，得到了具有强效抗结核活性的噻唑并吡啶酮脲类，其通过抑制DNA促旋酶B的ATP酶活性发挥作用。通过从噻唑并吡啶酮的N-4位延伸取代基引入结构多样性，以在促旋酶B的ATP结合区域的核糖口袋中形成疏水相互作用。进一步优化与促旋酶B活性位点口袋2位精氨酸的氢键相互作用，导致对该酶的强效抑制（IC50为2 nM）以及对结核分枝杆菌（Mtb）的强效细胞活性（MIC = 0.1 μM）。口服给药在急性小鼠结核病模型中证明了其疗效。
Zotero 插件