Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase
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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Several synthetic products derived from enfumafungin are currently under development to optimize in vivo antifungal activity and oral efficacy.
“Several synthetic products derived from enfumafungin are currently under development in order to optimize in vivo antifungal activity and oral efficacy [57].”
From <i>Candida</i>Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [57]
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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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