Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity.,ACS Infectious Diseases

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Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-03-02 , DOI: 10.1021/acsinfecdis.9b00277
Baptiste Villemagne ₁ , Arnaud Machelart ₂ , Ngoc Chau Tran ₁ , Marion Flipo ₁ , Martin Moune ₂ , Florence Leroux ₁ , Catherine Piveteau ₁ , Alexandre Wohlkönig _{3,

4} , René Wintjens ₅ , Xue Li ₆ , Ruxandra Gref ₆ , Priscille Brodin ₂ , Benoit Deprez ₁ , Alain R Baulard ₂ , Nicolas Willand ₁

Affiliation

Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug-resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure-activity and structure-property relationships in this chemical family. By combining structure-based drug design and in vitro evaluation of the compounds, we identified a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.

中文翻译：

具有体内乙硫酰胺增强活性的基于片段的优化EthR抑制剂。

结核病每年造成超过100万人死亡，仍然是单一传染病致死的主要原因。结核分枝杆菌的多药耐药菌株日益增加的威胁强调了对替代疗法的需求。分枝杆菌转录调节子EthR参与二线药物乙硫酰胺的生物活化控制。我们以前曾报道通过基于片段的方法发现乙酰胺的体外纳摩尔促进剂。在这项研究中，我们进一步探讨了该化学家族中的结构-活性和结构-性质之间的关系。通过将基于结构的药物设计和化合物的体外评估相结合，我们确定了一种新的恶二唑化合物作为第一个基于片段的乙酰胺增强剂，被证明在体内具有活性，

更新日期：2020-03-03

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