Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase
Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase
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DOI：
10.1016/j.bmcl.2012.05.031
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发表时间：
2012-11-15
影响因子：
2.7
通讯作者：
Kahn, Jennifer Nielsen
中科院分区：
文献类型：
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作者：
Heasley, Brian H.;Pacofsky, Gregory J.;Kahn, Jennifer Nielsen
口服生物可利用的 β-(1,3)-D-葡聚糖合酶抑制剂已被视为适合免疫功能低下患者治疗的新型广谱杀菌疗法。为此，基于三萜糖苷天然产物enfumafungin的半合成衍生化，建立了药物化学合作项目，以优化体内抗真菌活性和口服吸收特性。在这些研究过程中，假设半合成的 enfumafungin 类似物 3 的药代动力学特性可以通过将靠近 C3-氨基醚侧链碱性氮的烷基束缚到氮杂环系统中来改善，从而防止氧化 N-去甲基化。本文公开了这项研究工作的结果。 (C) 2012 Elsevier Ltd. 保留所有权利。
Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.