Pyridinium Modified Anthracenes and Their Endoperoxides Provide a Tunable Scaffold with Activity against Gram-Positive and Gram-Negative Bacteria,ACS Infectious Diseases

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Pyridinium Modified Anthracenes and Their Endoperoxides Provide a Tunable Scaffold with Activity against Gram-Positive and Gram-Negative Bacteria
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-07-22 , DOI: 10.1021/acsinfecdis.1c00263
Xuan Wang ₁ , Tamara Bittner ₁ , Martin Milanov _{2,

3,

4} , Laurine Kaul _{5,

6} , Stephan Mundinger ₁ , Hans-Georg Koch ₂ , Claudia Jessen-Trefzer ₁ , Henning J Jessen _{1,

7}

Affiliation

Due to the emergence of multidrug resistant bacteria, the development of new antibiotics is required. We introduce here asymmetrically modified positively charged bis(methylpyridinium) anthracenes as a novel tunable scaffold, in which the two positive charges can be placed at a defined distance and angle. Our structure–activity relationship reveals that coupling the methylpyridiniums with alkynyl linkers to the central anthracene unit yields antibacterial compounds against a wide range of bacteria, including Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis. Also, different mycobacteria, such as Mycobacterium smegmatis and Mycobacterium tuberculosis, are efficiently targeted by these compounds. The antibacterial activity depends on the number of alkynyl linkers and consequently also on the distance of the positive charges in the rigid anthracene scaffold. Additionally, the formation of an anthracene endoperoxide further increases the antibacterial activity, likely due to the release of toxic singlet oxygen that converts the endoperoxide back to the antibacterial anthracene scaffold with half-lives of several hours.

中文翻译：

吡啶修饰的蒽及其内过氧化物提供具有抗革兰氏阳性和革兰氏阴性细菌活性的可调支架

由于多重耐药菌的出现，需要开发新的抗生素。我们在这里介绍了不对称修饰的带正电荷的双（甲基吡啶）蒽作为一种新型可调支架，其中两个正电荷可以放置在定义的距离和角度。我们的构效关系表明，将带有炔基接头的甲基吡啶鎓与中央蒽单元偶联可产生抗菌化合物，以对抗多种细菌，包括大肠杆菌、金黄色葡萄球菌和表皮葡萄球菌。此外，不同的分枝杆菌，如耻垢分枝杆菌和结核分枝杆菌，被这些化合物有效地靶向。抗菌活性取决于炔基接头的数量，因此也取决于刚性蒽支架中正电荷的距离。此外，蒽内过氧化物的形成进一步增加了抗菌活性，这可能是由于有毒单线态氧的释放，将内过氧化物转化回抗菌蒽支架，半衰期为几个小时。

更新日期：2021-08-13

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