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

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 (1–4) and from D. araucarioides (5–10), hexamethyl-amentoflavone (11), cupressuflavone (12), and apigenin derivatives (13–23). 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.