Omelchuk Olga, Bychkova Elena, Efimova Svetlana, Grammatikova Natalia, Zatonsky George, Dezhenkova Lyubov, Solovieva Svetlana, Ostroumova Olga, Tevyashova Anna, Shchekotikhin Andrey
Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia.
Institute of Cytology of Russian Academy of Sciences, 4 Tikhoretsky Ave., St. Petersburg 194064, Russia.
Antibiotics (Basel). 2024 Dec 4;13(12):1177. doi: 10.3390/antibiotics13121177.
: In 2022, the World Health Organization highlighted the necessity for the development of new antifungal agents. Polyene antibiotics are characterized by a low risk of drug resistance; however, their use is limited by low solubility and severe side effects. : A series of -alkylated derivatives of amphotericin B and nystatin A as well as their -(2-hydroxyethyl)amides were synthesized. Their antifungal activity was evaluated against various strains and using the broth microdilution method. Cytotoxicity was assessed using an MTT assay on human embryonic kidney cells HEK293 and human skin fibroblast cells hFB-hTERT6, as well as a hemolysis assay on erythrocytes. Membrane activity was analyzed by fluorimetric measurement of calcein leakage from model liposomes. : Derivatives containing the -(hydroxyethyl)amino)ethyl fragment (compounds and ) exhibited relatively high antifungal activity, as did -(2-hydroxyethyl)amides and . Bis-modified compounds and did not outperform their mono-modified analogues in terms of activity or cytotoxicity. The mono--alkylated compound showed the highest activity/toxicity ratio, which correlated well with its selectivity for ergosterol-containing model membranes. : Combining two successful modifications does not necessarily improve the activity/toxicity ratio of polyenes. Further studies can be performed for the optimization of carboxyl group of .
2022年，世界卫生组织强调了开发新型抗真菌药物的必要性。多烯抗生素的特点是耐药风险低；然而，它们的使用受到低溶解度和严重副作用的限制。合成了一系列两性霉素B和制霉菌素A的 -烷基化衍生物及其 -(2-羟乙基)酰胺。使用肉汤微量稀释法评估了它们对各种菌株和 的抗真菌活性。使用MTT法对人胚肾细胞HEK293和人皮肤成纤维细胞hFB-hTERT6进行细胞毒性评估，并对红细胞进行溶血试验。通过荧光测量模型脂质体中钙黄绿素的泄漏来分析膜活性。含有 -(羟乙基)氨基)乙基片段的衍生物（化合物 和 ）表现出相对较高的抗真菌活性， -(2-羟乙基)酰胺 和 也是如此。双修饰化合物 和 在活性或细胞毒性方面并不优于其单修饰类似物。单 -烷基化化合物 显示出最高的活性/毒性比，这与其对含麦角固醇的模型膜的选择性密切相关。结合两种成功的修饰不一定能提高多烯的活性/毒性比。可以对 的羧基进行优化以开展进一步研究。
