There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure-activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC90 values against Escherichia coli (0.5-1 μg/mL) and Acinetobacter baumannii (8-16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.

中文翻译：

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发现和优化含吲哚基的4-羟基-2-吡啶酮II型DNA拓扑异构酶抑制剂，可有效抵抗多药耐药革兰氏阴性菌。

迫切需要确定针对多药耐药性（MDR）细菌感染，特别是革兰氏阴性病原体引起的细菌感染的新化学实体（NCE）。4-羟基-2-吡啶酮代表了一类对MDR革兰氏阴性细菌有活性的细菌II型拓扑异构酶的新型非氟喹诺酮抑制剂。在本文中，我们报告了一系列融合的吲哚基含4-羟基-2-吡啶酮的发现与构效关系，这些化合物具有改善的对氟喹诺酮耐药菌株的体外抗菌活性。化合物6o和6v代表此类化合物，同时靶向细菌DNA促旋酶和拓扑异构酶IV（Topo IV）。在简化的药敏筛选中，化合物6o和6v对大肠杆菌的MIC90值有所提高（0。与前体化合物相比，浓度为5-1μg/ mL）和鲍曼不动杆菌（8-16μg/ mL）。在鼠类败血病模型中，两种化合物在感染致死剂量大肠杆菌的小鼠中均显示出完全的保护作用。