Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics.,ACS Infectious Diseases

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Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-06-29 , DOI: 10.1021/acsinfecdis.0c00068
Anna N Tevyashova _{1,

2} , Elena N Bychkova ₁ , Svetlana E Solovieva ₁ , George V Zatonsky ₁ , Natalia E Grammatikova ₁ , Elena B Isakova ₁ , Elena P Mirchink ₁ , Ivan D Treshchalin ₁ , Eleonora R Pereverzeva ₁ , Evgeny E Bykov ₁ , Svetlana S Efimova ₃ , Olga S Ostroumova ₃ , Andrey E Shchekotikhin _{1,

2}

Affiliation

Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that N-(2-aminoethyl)amide of AmB (amphamide, 6) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound 6 had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (1). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.

中文翻译：

发现第二代多烯抗生素的候选药物安非他明。

两性霉素B（AmB，1）是治疗最严重的全身性真菌或原生动物感染的首选药物。然而，其应用受到在水性介质中的低溶解度和严重的副作用（例如与输注相关的反应，溶血毒性和肾毒性）的限制。由于这些限制，必须寻找具有更好化学治疗性能的多烯衍生物。为了获得具有较低自聚集和改善的溶解度的AmB衍生物，我们合成了一系列在导入的残基中带有一个额外碱性基团的AmB酰胺。体外抗真菌活性的筛选显示AmB的N-（2-氨基乙基）酰胺（amphamide，6）具有比父系AmB更好的抗真菌活性。小鼠的临床前研究证实，与AmB（1）相比，化合物6在小鼠念珠菌败血症模型中具有低得多的急性毒性和更高的抗真菌功效。因此，发现的两性酰胺是第二代多烯抗生素的有希望的候选药物，并且对于深入的临床前和临床评估也是有希望的。

更新日期：2020-08-14

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