Abstract
Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1-acetyllycorine exhibited the most potent anti-DENV activity (EC50=0.4 μM) with a reduced cytotoxicity (CC50>300 μM), which resulted in a selectivity index (CC50/EC50) of more than 750. The ketones 1-acetyl-2-oxolycorine (EC50=1.8 μM) and 2-oxolycorine (EC50=0.5 μM) also exhibited excellent antiviral activities with low cytotoxicity. Structure-activity relationships for the lycorine derivatives against DENV are discussed. A three-dimensional quantitative structure-activity relationship model was established by using a comparative molecular-field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties. Alkaloids that bite back: Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. Currently, vaccines or specific therapeutics are not available. Lycorine, which is a natural alkaloid, has reportedly demonstrated biological activity against dengue virus (DENV). A series of lycorine derivatives and their anti-DENV activities are reported herein.
Original language | English (US) |
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Pages (from-to) | 1522-1533 |
Number of pages | 12 |
Journal | ChemMedChem |
Volume | 9 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2014 |
Externally published | Yes |
Keywords
- alkaloids
- antiviral agents
- dengue virus
- lycorine
- structure-activity relationships
ASJC Scopus subject areas
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Molecular Medicine
- Biochemistry
- Pharmacology
- Organic Chemistry