First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors
First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors
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DOI：
10.1016/j.bmcl.2019.05.003
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发表时间：
2019-07-15
影响因子：
2.7
通讯作者：
Duerfeldt, Adam S.
中科院分区：
文献类型：
--
作者：
Li, Yangxiong;Gardner, Jessi J.;Duerfeldt, Adam S.
细菌双组分信号转导系统 CpxRA 的基因激活消除了人类和小鼠感染模型中许多病原体的毒力。最近，2,3,4,9-四氢-1H-咔唑-1-胺被证明可以通过抑制 CpxA 的磷酸酶活性来激活 CpxRA 系统。在此，我们通过关注三种方法报告了该支架的初始构效关系：1）A环取代，2）B环解构以提供N-芳基化氨基酸衍生物，以及3）C环消除以得到2-乙氨基取代的吲哚。这些研究表明，A 环易于功能化，并为持续优化该化学型提供了一条有希望的途径。进一步的研究表明，C 环对于活性不是必需的，尽管它可能提供有利于效力的构象约束，并且伯胺需要 (R) 立体化学。通过解构 B 环来简化支架，得到无活性的化合物，凸显了吲哚核心的重要性。鉴定出一种新的先导化合物 26，其 CpxA 磷酸酶抑制效果比初始化合物提高了 30 倍。对膜渗透性和流出能力不同的细菌菌株中的氨基和脱氨基衍生物的比较表明，胺不仅是靶标结合所必需的，而且也是大肠杆菌中渗透和积累所必需的。
Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a similar to 30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.