Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy.
Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019, Castelnuovo, Berardenga, Italy.
Sci Rep. 2017 Aug 15;7(1):8251. doi: 10.1038/s41598-017-08749-6.
In the last two decades, the repertoire of clinically effective antibacterials is shrinking due to the rapidly increasing of multi-drug-resistant pathogenic bacteria. New chemical classes with innovative mode of action are required to prevent a return to the pre-antibiotic era. We have recently reported the identification of a series of linear guanidine derivatives and their antibacterial properties. A batch of a promising candidate for optimization studies (compound 1) turned out to be a mixture containing two unknown species with a better biological activity than the pure compound. This serendipitous discovery led us to investigate the chemical nature of the unknown components of the mixture. Through MS analysis coupled with design and synthesis we found that the components were spontaneously generated oligomers of the original compound. Preliminary biological evaluations eventually confirmed the broad-spectrum antibacterial activity of this new family of molecules. Interestingly the symmetric dimeric derivative (2) exhibited the best profile and it was selected as lead compound for further studies.
在过去的二十年中，由于多药耐药病原菌的迅速增加，临床上有效的抗菌药物种类不断减少。需要具有创新作用模式的新型化学类别来防止回到抗生素前时代。我们最近报道了一系列线性胍衍生物的鉴定及其抗菌特性。一批有希望进行优化研究的候选药物（化合物 1）结果是一种含有两种未知物质的混合物，其生物活性优于纯化合物。这一偶然发现促使我们研究混合物中未知成分的化学性质。通过 MS 分析以及设计和合成，我们发现这些成分是原始化合物的自发生成的寡聚物。初步的生物学评估最终证实了这一家族分子具有广谱抗菌活性。有趣的是，对称二聚体衍生物（2）表现出最佳的特性，因此被选为进一步研究的先导化合物。
