Department of Biotechnology, Chemistry, and Pharmacy , University of Siena , I-53100 Siena , Italy.
Department of Medical Biotechnology , University of Siena , I-53100 Siena , Italy.
J Med Chem. 2018 Oct 25;61(20):9162-9176. doi: 10.1021/acs.jmedchem.8b00619. Epub 2018 Oct 11.
Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gram-negative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.
如今，越来越多的多药耐药病原菌对公众健康构成了严重威胁，而新抗生素的缺乏正成为全球紧急情况。因此，迫切需要在抗菌领域开展研究，以扩大现有药物库。我们最近报道了一种烷基胍衍生物（2），其具有对称二聚体结构，是进一步开发的良好候选物，对革兰氏阳性和革兰氏阴性菌株均具有很高的抗菌活性。在这项研究中，我们从其化学结构出发，合成了一个小分子类似物库。此外，对一些选定的衍生物进行了生物学和体外药代动力学特性研究，揭示了其显著的特性：广谱特性、对耐药临床分离株的活性以及可接受的水溶解度。有趣的是，2 似乎既不会选择耐药菌株，也不会宏观改变细胞膜，但需要进一步研究来确定其作用模式。
