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DOI: 10.1055/s-0031-1298355
© Georg Thieme Verlag KG Stuttgart · New York
Biflavonoids of Dacrydium balansae with Potent Inhibitory Activity on Dengue 2 NS5 Polymerase
Publication History
received Nov. 14, 2011
revised February 13, 2012
accepted February 15, 2012
Publication Date:
12 March 2012 (online)
Abstract
In order to find new molecules for antiviral drug design, we screened 102 ethyl acetate extracts from New-Caledonian flora for antiviral activity against the dengue 2 virus RNA-dependant RNA polymerase (DV-NS5 RdRp). The leaf extract of Dacrydium balansae, which strongly inhibited the DV-NS5, was submitted to bioguided fractionation. Four biflavonoids (1–4), three sterols (5–7), and two stilbene derivatives (8–9) were identified and evaluated for their antiviral potential on the DV-NS5 RdRp. Biflavonoids appeared to be potent inhibitors of DV-NS5 RdRp with IC50s between 0.26 and 3.12 µM. Inhibitory activity evaluations against the RNA polymerase from other Flaviviridae viruses allowed us to conclude that these compounds are specific inhibitors of the DV RNA polymerase. The strongest inhibitions were observed with hinokiflavone (4), but podocarpusflavone A (2) is the strongest noncytotoxic inhibitor of the DV-NS5 and it also displayed polymerase inhibitory activity in a DV replicon. A preliminary structure-activity relationship study (SARs) revealed the necessity of the biflavonoid skeleton, the influence of number and position of methoxylations, and the importance of a free rotation of the linkage between the two apigenin monomers of the biflavonoids. To the best of our knowledge, podocarpusflavone A (2) is the strongest noncytotoxic non-nucleotide molecule exhibiting a specific inhibitory activity against the RNA polymerase domain of DV-NS5 and thus is promising for chemotherapy development against dengue fever.
Key words
biflavonoids - Dacrydium balansae - Podocarpaceae - dengue virus - DV-NS5 RdRp
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Mohammed Nour
Laboratoire Insulaire du Vivant et de l'Environnement
Université de la Nouvelle-Caledonie, BP R4
Campus de Nouville
98851 Nouméa Cedex
Nouvelle-Calédonie, France
Phone: +687 29 02 52
Fax: +687 25 48 29
Email: nour@univ-nc.nc