Nicotinamide adenine dinucleotide kinases (NAD kinases) are essential and ubiquitous enzymes involved in the production of NADP(H) which is an essential cofactor in many metabolic pathways. Targeting NAD kinase (NADK), a rate limiting enzyme of NADP biosynthesis pathway, represents a new promising approach to treat bacterial infections. Previously, we have produced the first NADK inhibitor active against staphylococcal infection. From this linear di-adenosine derivative, namely NKI1, we designed macrocyclic analogues. Here, we describe the synthesis and evaluation of an original series of cyclic diadenosine derivatives as NADK inhibitors of two pathogenic bacteria, Listeria monocytogenes and Staphylococcus aureus. The nature and length of the link between the two adenosine units were examined leading to sub-micromolar inhibitors of NADK1 from L. monocytogenes, including its most potent in vitro inhibitor reported so far (with a 300-fold improvement compared to NKI1).

烟酰胺腺嘌呤二核苷酸激酶（NAD 激酶）是参与 NADP(H) 产生的必需且普遍存在的酶，NADP(H) 是许多代谢途径中的必需辅助因子。靶向 NAD 激酶 (NADK) 是一种 NADP 生物合成途径的限速酶，代表了一种治疗细菌感染的新方法。此前，我们已经生产出第一种对葡萄球菌感染具有活性的 NADK 抑制剂。从这种线性双腺苷衍生物，即 NKI1，我们设计了大环类似物。在这里，我们描述了原始系列环二腺苷衍生物的合成和评估，作为两种致病菌单核细胞增生李斯特菌和金黄色葡萄球菌的 NADK 抑制剂. 研究了两个腺苷单元之间连接的性质和长度，导致来自单核细胞增生李斯特氏菌的 NADK1 亚微摩尔抑制剂，包括迄今为止报道的最有效的体外抑制剂（与 NKI1 相比提高了 300 倍）。