Discovery of new chemical entities as potential leads against Mycobacterium tuberculosis

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• 作者：Xiaoyun Lu^a ; ^b ; ^e ; ^{luxy2016@jnu.edu.cn} ; Jian Tang^b ; ^c ; ^e ; Zhiyong Liu^b ; ^c ; Minke Li^b ; Tianyu Zhang^b ; Xiantao Zhang^d ; Ke Ding^a ; ^b
• 关键词：Anti-tubercular agent ; Imidazo[21-b]thiazole ; Pyrazolo[51-b]thiazole ; Scaffold hopping
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：26
• 期：24
• 页码：5916-5919
• 全文大小：543 K
• 卷排序：26

文摘

A series of biheterocyclic (1H-indole, benzofuran, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyrimidin-5(4H)-one, imidazo[2,1-b]thiazole and pyrazolo[5,1-b]thiazole) derivatives were synthesized and evaluated for their anti-tubercular activities. The imidazo[2,1-b]thiazoles 9a–c and pyrazolo[5,1-b]thiazoles 10a–c exhibited promising anti-tubercular activity in varying degrees. Especially, the 2,6-dimethylpyrazolo[5,1-b]thiazole 10a exhibited strong suppressing function against H37Ra strain with MIC value of 0.03 μg/mL. Compound 10a also displayed good pharmacokinetic profiles with oral bioavailability (F) of 41.7% and a half-life of 13.4 h. Furthermore, 10a significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model, suggesting its promising potential for development of anti-tubercular drugs.