N-1 取代的 1,5-萘啶-2-酮类似物的构效关系，作为新型氧杂双环辛烷连接的细菌拓扑异构酶抑制剂的广谱抗菌剂（第 9 部分）。
Structure activity relationship of N-1 substituted 1,5-naphthyrid-2-one analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-9).
机构信息
Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Merck & Co., Inc., Kenilworth, NJ 07033, USA.
出版信息
Bioorg Med Chem Lett. 2022 Nov 1;75:128808. doi: 10.1016/j.bmcl.2022.128808. Epub 2022 May 21.
Novel bacterial topoisomerase inhibitors (NBTIs) are the newest members of gyrase inhibitor broad-spectrum antibacterial agents, represented by the most advanced member, gepotidacin, a 4-amino-piperidine linked NBTI, which is undergoing phase III clinical trials for treatment of urinary tract infections (UTI). We have extensively reported studies on oxabicyclooctane linked NBTIs, including AM-8722. The present study summarizes structure activity relationship (SAR) of AM-8722 leading to identification of 7-fluoro-1-cyanomethyl-1,5-naphthyridin-2-one based NBTI (16, AM-8888) with improved potency and spectrum (MIC values of 0.016-4 μg/mL), with Pseudomonas aeruginosa being the least sensitive strain (MIC 4 μg/mL).
新型细菌拓扑异构酶抑制剂（NBTIs）是回旋酶抑制剂类广谱抗菌药物中的最新成员，以最先进的成员 gepotidacin 为代表，它是一种连接 4-氨基哌啶的 NBTI，目前正在进行治疗尿路感染（UTI）的 III 期临床试验。我们已经广泛报道了关于氧杂双环辛烷连接的 NBTIs 的研究，包括 AM-8722。本研究总结了 AM-8722 的构效关系（SAR），从而确定了基于 7-氟-1-氰甲基-1,5-萘啶-2-酮的 NBTI（16，AM-8888），其具有更好的活性和广谱性（MIC 值为 0.016-4μg/mL），铜绿假单胞菌是最不敏感的菌株（MIC 为 4μg/mL）。
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