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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity.
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Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity.

机译：溴甲基取代的支架的合成和应用，可用于高效优化抗毒活性。

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摘要

Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Abeta aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.
机译：杀微生物剂是一类化合物，其通过阻断大肠杆菌中的伴侣/诱导途径来减弱革兰氏阴性细菌的毒力。还已经表明，由杀人剂所基于的拟肽支架衍生的化合物可以防止Abeta聚集和卷曲的形成。为了促进针对不同靶标的优化，已经开发了一种新的合成平台，该平台能够在肽模拟支架上的C-7位快速简便地引入各种取代基。重要的是，该策略还可以在该位置引入以前无法实现的杂原子。合成策略的关键是环稠合的二氢噻唑啉2-吡啶酮杀菌剂支架的C-7溴甲基取代的衍生物的合成。从这种通用的反应性中间体，可以将各种杂原子连接的取代基引入到支架上，包括胺，醚，酰胺和磺酰胺。另外，可以通过Suzuki-Miyaura交叉偶联将碳-碳键引入sp（3）-杂交的溴甲基取代的支架。在全细菌试验中对24 C-7取代化合物的评估提供了重要的结构活性数据，并导致鉴定出许多新杀虫剂，其活性与先前开发的杀虫剂相同或更好。

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