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Simple amphiphilic α-hydrazido acids: Rational design, synthesis, and in vitro bioactivity profile of a novel class of potential antimicrobial compounds.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.ejmech.2020.112072 Paolo Amabili 1 , Francesca Biavasco 2 , Andrea Brenciani 3 , Barbara Citterio 2 , Dario Corbisiero 4 , Lucia Ferrazzano 4 , Simona Fioriti 3 , Giulia Guerra 1 , Mario Orena 1 , Samuele Rinaldi 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.ejmech.2020.112072 Paolo Amabili 1 , Francesca Biavasco 2 , Andrea Brenciani 3 , Barbara Citterio 2 , Dario Corbisiero 4 , Lucia Ferrazzano 4 , Simona Fioriti 3 , Giulia Guerra 1 , Mario Orena 1 , Samuele Rinaldi 1
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Pursuing the search for a new class of structurally simple mimics of antimicrobial peptides, we optimized a short, cheap and high-yielding synthesis of mono-charged amphiphilic α-hydrazido acid derivatives. The most active derivatives furnished MICs that are among the best values reported in literature for synthetic amphiphilic membranolytic compounds. They exhibited a broad-spectrum in vitro activity against a variety of Gram-positive and Gram-negative bacteria, including two multidrug-resistant strains. In spite of the minimal cationic charge, the best compounds demonstrated to be selective toward bacterial cell membranes over mammalian cell membranes. The relationship between either the antibacterial or the hemolytic activity and the overall lipophilicity furnished an easy way to individuate the best dimensional range for the hydrophobic portions. The importance of a non-disrupted amphiphilicity was also demonstrated. Considering the bioactivity profile and the ease of synthesis, these chemically and proteolitically stable hydrochlorides are suitable for development of a new class of wide-spectrum antibiotics.
中文翻译：
简单的两亲性α-肼基酸：合理设计，合成和新型潜在抗菌化合物的体外生物活性。
为了寻找一类新的结构简单的抗菌肽模拟物，我们优化了单电荷两亲性α-肼基酸衍生物的短时，廉价和高收率合成。活性最高的衍生物提供的MIC均为文献中报道的合成两亲性膜分解化合物的最佳值。它们对多种革兰氏阳性和革兰氏阴性细菌（包括两种耐多药菌株）表现出广谱的体外活性。尽管阳离子电荷最少，但最好的化合物对哺乳动物细胞膜的细菌细胞膜具有选择性。抗菌或溶血活性与总体亲脂性之间的关系为区分疏水部分的最佳尺寸范围提供了一种简便的方法。还证明了不间断的两亲性的重要性。考虑到生物活性特征和易于合成，这些化学和蛋白稳定的盐酸盐适合开发新型的广谱抗生素。
更新日期：2020-01-21
中文翻译：
简单的两亲性α-肼基酸：合理设计，合成和新型潜在抗菌化合物的体外生物活性。
为了寻找一类新的结构简单的抗菌肽模拟物，我们优化了单电荷两亲性α-肼基酸衍生物的短时，廉价和高收率合成。活性最高的衍生物提供的MIC均为文献中报道的合成两亲性膜分解化合物的最佳值。它们对多种革兰氏阳性和革兰氏阴性细菌（包括两种耐多药菌株）表现出广谱的体外活性。尽管阳离子电荷最少，但最好的化合物对哺乳动物细胞膜的细菌细胞膜具有选择性。抗菌或溶血活性与总体亲脂性之间的关系为区分疏水部分的最佳尺寸范围提供了一种简便的方法。还证明了不间断的两亲性的重要性。考虑到生物活性特征和易于合成，这些化学和蛋白稳定的盐酸盐适合开发新型的广谱抗生素。
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