Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of ¦Â-1,3-glucan synthase
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- 作者：Brian H. Heasley ; Gregory J. Pacofsky ; Ahmed Mamai ; Hao Liu ; Kingsley Nelson ; Ghjuvanni Coti ; Michael R. Peel ; James M. Balkovec ; Mark L. Greenlee ; Paul Liberator ; Dongfang Meng ; Dann L. Parker ; Robert R. Wilkening ; James M. Apgar ; F. Racine ; Ming Jo Hsu ; Robert A. Giacobbe ; Jennifer Nielsen Kahn
- 关键词：Enfumafungin ; ¦Â-1 ; 3-Glucan synthase ; Triterpenoid glycoside ; Antifungal agents ; Medicinal chemistry ; Oral bioavailability
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 November, 2012
- 年：2012
- 卷：22
- 期：22
- 页码：6811-6816
- 全文大小：813 K
文摘
Orally bioavailable inhibitors of ¦Â-(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.