Cited by 37Antifungal resistance and susceptibilityNatural product bioactivities and synthesisMicrobial Natural Products and Biosynthesis

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

Heasley, Brian H., Pacofsky, Gregory J., Mamai, Ahmed, Liu, Hao, Nelson, Kingsley, Coti, Ghjuvanni, Peel, Michael R., Balkovec, James M. +10 more·2012·Bioorganic & Medicinal Chemistry Letters

Abstract

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.

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Crossref · 10.1016/j.bmcl.2012.05.031

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Authors
Heasley, B. H., Pacofsky, G. J., Mamai, A., Liu, H., Nelson, K., Coti, G., Peel, M. R., Balkovec, J. M., Greenlee, M. L., Liberator, P., Meng, D., Parker, D. L., Wilkening, R. R., Apgar, J. M., Racine, F., Hsu, M. J., Giacobbe, R. A., & Kahn, J. N.
Affiliations
  • Scynexis (United States) (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Heasley, Brian H.
Venue
Bioorganic & Medicinal Chemistry Letters
Publisher
Elsevier BV
Published
2012-11
Volume
22
Issue
22
Pages
6811-6816
ISSN
0960-894X (ISSN-L)
OpenAlex
W2089162191
Cited by
35
References
15
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 2
FWCI
1.99
Type
journal article
Language
en
Open access
closed
Locations
  • Bioorganic & Medicinal Chemistry Letters (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
  • Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
Keywords
antifungal agents, oral bioavailability, triterpenoid saponins, immunocompromised patients, antifungal drug development
MeSH terms
Administration, Oral, Animals, Antifungal Agents, Candida albicans, Enzyme Inhibitors, Glucosyltransferases, Glycosides, Half-Life, Structure-Activity Relationship, Triterpenes, Mice

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