Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-07-03 , DOI: 10.1016/j.bioorg.2020.104069 Chen Belay 1 , Noam Y Steinman 1 , Luis M Campos 2 , Ron Dzikowski 3 , Jacob Golenser 3 , Abraham J Domb 1
Cationic molecules are found in abundance as antimicrobial agents with a well-defined mechanism of action and significant therapeutic benefits. Quaternary ammonium-containing compounds are frequently employed due to their facile synthesis and tunable properties. Over time, however, bacterial resistance to these compounds has become a significant obstacle. We report here a series of asymmetric trisalkylamine cyclopropenium cationic derivatives as chemical isosteres of quaternary ammonium compounds, capable of strong antimicrobial activity and overcoming microbial resistance. These small molecules were prepared by one-pot reaction of tetrachlorocyclopropene (TCC) with unhindered secondary amines in the presence of Hünig’s base. In this work we describe the synthesis, purification, and characterization of five trisamino-cyclopropenium derivatives and confirm their structures by spectral analysis and mass-spectrometry. Three of the compounds displayed considerable antimalarial activity (IC50 < 0.1 µM) without demonstrating significant toxic effects in vitro (TC50 > 1 µM). This class of cyclopropenium-based compounds provides an opening for the discovery of potent and non-toxic antimicrobial agents.
中文翻译:
具有抗菌活性的不对称三烷基胺环丙烯衍生物。
阳离子分子被广泛用作抗菌剂,具有明确的作用机理和显着的治疗益处。含季铵化合物由于易于合成和可调性而经常使用。然而,随着时间的流逝,细菌对这些化合物的抗性已成为重要的障碍。我们在这里报告了一系列不对称的三烷基胺环丙烯阳离子衍生物,作为季铵化合物的化学等排体,具有很强的抗菌活性并能克服微生物的耐药性。这些小分子是通过四氯环丙烯(TCC)与不受阻碍的仲胺在Hünig碱存在下的一锅反应制备的。在这项工作中,我们描述了合成,纯化,五种三氨基环丙烯衍生物的合成和表征,并通过光谱分析和质谱确定其结构。其中三种化合物显示出显着的抗疟活性(IC50 <0.1 µM),而没有表现出明显的体外毒性作用(TC 50 > 1 µM)。这类基于环丙烯的化合物为有效和无毒的抗菌剂的发现提供了机会。