Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis

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• 作者：Rongjun He ; Zhi-Hong Yu ; Ruo-Yu Zhang ; Li Wu ; Andrea M. Gunawan ; Zhong-Yin Zhang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：6
• 期：12
• 页码：1231-1235
• 全文大小：328K
• ISSN：1948-5875

文摘

mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified 伪-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation 尾-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. Structure-guided and fragment-based optimization of SPAA led to the most potent and selective mPTPB inhibitor 9, with a K_i of 7.9 nM and more than 10,000-fold preference for mPTPB over a large panel of 25 phosphatases. Compound 9 also exhibited excellent cellular activity and specificity in blocking mPTPB function in macrophage. Given its novel structure, modest molecular mass, and extremely high ligand efficiency (0.46), compound 9 represents an outstanding lead compound for anti-TB drug discovery targeting mPTPB.