A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.

将 2-（三氟甲基）吡啶的新衍生物作为细菌靶标 PqsR 针对铜绿假单胞菌的有效反向激动剂的一条短而不同的途径描述了 (PA) 感染。这种革兰氏阴性病原体会导致严重的医院感染，并且由于耐药性问题，常见的抗生素治疗方案无效。基于较早确定的优化命中，我们使用两个中心构建块进行了衍生化和刚性化尝试。分子的西部部分是通过配备末端炔烃的 2-(三氟甲基)吡啶头基建立的。然后通过利用 Sonogashira 和 Suzuki 型化学的 aryliode 图案引入东部部分。随后的修改提供了对一系列化合物的快速访问，允许深入了解 SAR，并能够将命中支架优化为具有纳摩尔效力的先导结构，并结合有利的体外ADME/T 特征。