Planta Med 2012; 78(7): 672-677
DOI: 10.1055/s-0031-1298355
Biological and Pharmacological Activity
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Biflavonoids of Dacrydium balansae with Potent Inhibitory Activity on Dengue 2 NS5 Polymerase

Paul Coulerie1 , Cécilia Eydoux2 , Edouard Hnawia1 , Laetitia Stuhl2 , Alexandre Maciuk3 , Nicolas Lebouvier1 , Bruno Canard2 , Bruno Figadère3 , Jean-Claude Guillemot2 , Mohammed Nour1
  • 1Laboratoire Insulaire du Vivant et de l'Environnement, Université de la Nouvelle-Caledonie, Nouméa Cedex – Nouvelle-Calédonie, France
  • 2AFMB, UMR 6098, Aix-Marseille Université, Campus de Luminy, Marseille Cedex 09, France
  • 3Laboratoire de Pharmacognosie-Chimie des substances naturelles et chimiothérapies antiparasitaires, UMR CNRS 8076 BioCIS, Université Paris-Sud XI, Clément, Châtenay-Malabry, France
Further Information

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 (14), three sterols (57), and two stilbene derivatives (89) 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.

Supporting Information

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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

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