The developing antibiotic resistance crisis creates a serious need for new antimicrobial agents. In this work, novel nitroaromatic-protected piperazine diazeniumdiolate (nitric oxide donor) prodrugs are synthesized to release nitric oxide upon enzyme activation to kill bacteria. Antibacterial prodrugs could help reduce side effects due to antibiotics, only releasing the therapeutic where infections are concentrated. The nitroreductase enzyme, which is found almost exclusively in bacteria, reduces the nitroaromatic-protecting group of the synthesized compounds and catalyzes the release of nitric oxide. This paper shows that nitric oxide release from the synthesized compounds only occurs in the presence of a bacteria-derived nitroreductase enzyme, demonstrating the possibility of site-specific delivery of an antibacterial therapeutic. The amount of nitric oxide release is measured at concentrations of 0.01, 0.1, and 1 mM, and is well within antibacterial levels at concentrations of 0.1 and 1 mM. The antibacterial activity of the compounds is demonstrated after exposure of the compounds to Escherichia coli, a nitroreductase-producing bacterial species, leading to up to a 94% reduction in the number of viable bacteria after 24 h at 1 mM concentrations of the prodrug. This study is the first example of an antibacterial diazeniumdiolate prodrug activated by a nitroreductase enzyme, and further demonstrates the possibilities of antibacterial prodrugs.

不断发展的抗生素耐药性危机使得人们迫切需要新的抗菌剂。在这项工作中，合成了新型的硝基芳香族保护的哌嗪二氮杂二氮烯鎓盐（一氧化氮供体）前药，可在酶激活后释放一氧化氮以杀死细菌。抗菌前药可以帮助减少由于抗生素引起的副作用，仅在感染集中的地方释放治疗剂。几乎仅在细菌中发现的硝基还原酶减少了合成化合物的硝基芳族保护基并催化一氧化氮的释放。本文表明，从合成化合物中释放出的一氧化氮仅在细菌衍生的硝基还原酶存在的情况下才会发生，这表明了特定位置递送抗菌药物的可能性。一氧化氮的释放量是在浓度为0.01、0.1和1 mM时测量的，并且在浓度为0.1和1 mM时处于抗菌水平之内。在将化合物暴露于以下物质后证明了该化合物的抗菌活性大肠杆菌，一种产生硝基还原酶的细菌，在浓度为1 mM的前药24小时后，导致存活细菌数量减少多达94％。该研究是被硝基还原酶激活的抗菌性二氮烯二醇二氮杂酸酯前药的第一个实例，并进一步证明了抗菌性前药的可能性。