In this work, we describe an improved series of -phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC values against DNA gyrase, and in addition, compound also inhibits topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds , , and show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate (VISA) and strains. Compound shows an inhibitory effect against the methicillin-resistant strain (MRSA) with a MIC of 0.0625 μg/mL and against the strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.

中文翻译：

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改进的 DNA 旋转酶 N-苯基吡咯酰胺抑制剂作为高优先级细菌菌株的抗菌剂


在这项工作中，我们描述了一系列改进的 β-苯基吡咯酰胺抑制剂，它们对 DNA 旋转酶表现出强大的活性，并且对高优先级革兰氏阳性菌非常有效。最有效的化合物对 DNA 旋转酶表现出低纳摩尔 IC50 值，此外，该化合物还在纳摩尔浓度范围内抑制拓扑异构酶 IV，使其成为开发这些酶的有效双重抑制剂的有希望的候选者。所有测试的化合物均对人类同种型 DNA 拓扑异构酶 IIα 表现出高度选择性。化合物 、 和 对万古霉素中间体 (VISA) 和菌株的 MIC 值在 0.031 至 0.0625 μg/mL 之间。化合物对甲氧西林耐药菌株 (MRSA) 具有抑制作用，MIC 为 0.0625 μg/mL，对 MRSA 菌株的 MIC 为 0.125 μg/mL。在时间杀灭测定中，化合物对 MRSA 菌株表现出剂量依赖性杀菌作用，并在 8 小时后达到 8 × MIC 的杀菌活性。化合物对MRSA菌株的抗生素后效应(PAE)持续时间为2小时，这对应于环丙沙星的PAE持续时间。在 MCF-7 乳腺癌细胞系上进行的 MTS 测定表明，这些化合物在有效浓度下没有细胞毒性。