Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 22; pp. 6811 - 6816
• Main Authors: Heasley, Brian H., Pacofsky, Gregory J., Mamai, Ahmed, Liu, Hao, Nelson, Kingsley, Coti, Ghjuvanni, Peel, Michael R., Balkovec, James M., Greenlee, Mark L., Liberator, Paul, Meng, Dongfang, Parker, Dann L., Wilkening, Robert R., Apgar, James M., Racine, F., Hsu, Ming Jo, Giacobbe, Robert A., Kahn, Jennifer Nielsen
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-11-2012; Elsevier
• Subjects: absorption; Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacokinetics; antifungal properties; Biological and medical sciences; Candida albicans - drug effects; derivatization; Enfumafungin; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Glucosyltransferases - antagonists & inhibitors; Glucosyltransferases - metabolism; glycosides; Glycosides - chemical synthesis; Glycosides - chemistry; Glycosides - pharmacokinetics; Half-Life; Medical sciences; Medicinal chemistry; Mice; nitrogen; Oral bioavailability; patients; pharmacokinetics; Pharmacology. Drug treatments; Structure-Activity Relationship; Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacokinetics; Triterpenoid glycoside; β-1,3-Glucan synthase; β-1,3-Glucan synthase; Medicinal chemistry; Oral bioavailability; Enfumafungin; Antifungal agents; Triterpenoid glycoside; Terpenoid; Enzyme; Transferases; Glycosyltransferases; Oral administration; 1,3-β-Glucan synthase; Bioavailability; Biological activity; Saponin; Antifungal agent; Triterpene; Hexosyltransferases; Glycoside; Inhibitor; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.031

Orally bioavailable inhibitors of β-(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.