Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment.,European Journal of Medicinal Chemistry

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Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-02 , DOI: 10.1016/j.ejmech.2019.112031
Jinhe Han ₁ , Hye Won Lee ₂ , Yifeng Jin ₁ , Daulat B Khadka ₁ , Suhui Yang ₁ , Xiaoli Li ₁ , Meehyein Kim ₂ , Won-Jea Cho ₁

Affiliation

Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 μM, but no cytotoxicity at 100 μM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 μM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.

中文翻译：

双酰胺衍生物作为亲环素A抑制剂用于HCV治疗的分子设计，合成和生物学评估。

丙型肝炎病毒（HCV）是终末期肝病的主要原因。直接作用抗病毒药物（DAA），包括非结构蛋白（NS3 / 4A蛋白酶，NS5A和NS5B聚合酶）的抑制剂，是抗HCV治疗的关键成分。但是，某些DAA与耐药性增加和不良副作用有关。先前的报道表明，双酰胺类可能是一类新型的亲环素A（CypA）抑制剂，可将HCV作为联合疗法的一部分进行治疗。为了充分阐明双酰胺衍生物的构效关系并找到具有不同结合方式的更好命中化合物，在对接程序的帮助下设计了16种双酰胺。然后使用一锅四组分Ugi反应合成它们。7e，选择性指数大于18.9（50％有效浓度为5.3μM，但没有选择100μM的细胞毒性）和可以潜入网守口袋的独特结合模式作为新的热门化合物。表面等离子体共振实验表明，7e能够以3.66μM的KD与CypA结合。综上所述，这些结果表明，将来7e作为CypA抑制剂可在组合疗法中用作替代的抗HCV药物。

更新日期：2020-01-02

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