Planta Med 2013; 79(14): 1313-1318
DOI: 10.1055/s-0033-1350672
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Structure-Activity Relationship Study of Biflavonoids on the Dengue Virus Polymerase DENV-NS5 RdRp

Paul Coulerie
1   Laboratoire Insulaire du Vivant et de lʼEnvironnement, Université de la Nouvelle-Calédonie, Nouméa, Nouvelle-Calédonie
,
Mohammed Nour
1   Laboratoire Insulaire du Vivant et de lʼEnvironnement, Université de la Nouvelle-Calédonie, Nouméa, Nouvelle-Calédonie
,
Alexandre Maciuk
2   Laboratoire de Pharmacognosie-Chimie des substances naturelles et chimiothérapies antiparasitaires, BioCIS, Université Paris-Sud, Châtenay-Malabry, France
,
Cécilia Eydoux
3   AFMB, Aix-Marseille Université, Campus de Luminy, Marseille, France
,
Jean-Claude Guillemot
3   AFMB, Aix-Marseille Université, Campus de Luminy, Marseille, France
,
Nicolas Lebouvier
1   Laboratoire Insulaire du Vivant et de lʼEnvironnement, Université de la Nouvelle-Calédonie, Nouméa, Nouvelle-Calédonie
,
Edouard Hnawia
1   Laboratoire Insulaire du Vivant et de lʼEnvironnement, Université de la Nouvelle-Calédonie, Nouméa, Nouvelle-Calédonie
,
Karine Leblanc
2   Laboratoire de Pharmacognosie-Chimie des substances naturelles et chimiothérapies antiparasitaires, BioCIS, Université Paris-Sud, Châtenay-Malabry, France
,
Guy Lewin
2   Laboratoire de Pharmacognosie-Chimie des substances naturelles et chimiothérapies antiparasitaires, BioCIS, Université Paris-Sud, Châtenay-Malabry, France
,
Bruno Canard
3   AFMB, Aix-Marseille Université, Campus de Luminy, Marseille, France
,
Bruno Figadère
2   Laboratoire de Pharmacognosie-Chimie des substances naturelles et chimiothérapies antiparasitaires, BioCIS, Université Paris-Sud, Châtenay-Malabry, France
› Author Affiliations
Further Information

Publication History

received 11 March 2013
revised 30 June 2013

accepted 05 July 2013

Publication Date:
08 August 2013 (online)

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Abstract

Dengue virus is the worldʼs most prevalent human pathogenic arbovirus. There is currently no treatment or vaccine, and solutions are urgently needed. We previously demonstrated that biflavonoids from Dacrydium balansae, an endemic gymnosperm from New Caledonia, are potent inhibitors of the Dengue virus NS5 RNA-dependent RNA polymerase. Herein we describe the structure-activity relationship study of 23 compounds: biflavonoids from D. balansae (14) and from D. araucarioides (510), hexamethyl-amentoflavone (11), cupressuflavone (12), and apigenin derivatives (1323). We conclude that 1) over the four different biflavonoid skeletons tested, amentoflavone (1) and robustaflavone (5) are the most promising ones for antidengue drug development, 2) the number and position of methyl groups on the biflavonoid moiety modulate their inhibition of Dengue virus NS5 RNA-dependent RNA polymerase, and 3) the degree of oxygenation of flavonoid monomers influences their antidengue potential. Sotetsuflavone (8), with an IC50 = 0.16 µM, is the most active compound of this series and is the strongest inhibitor of the Dengue virus NS5 RNA-dependent RNA polymerase described in the literature.

Supporting Information