<em>In Vitro</em> and <em>In Silico</em> Analyses Explore the Role of Flavonoid Classes in the Antiviral Activity of Plant Extracts Against the Dengue Virus

This study aimed to determine the association between the content of flavonoids and an-14 tiviral effect of plant extracts against the dengue virus (DENV). Extracts from medicinal plants cul-15 tivated in Colombia were prepared by ultrasonic-assisted solvent extraction (UAE) and supercritical 16 fluid extraction (SFE). UHPLC/ESI-Q-Orbitrap-MS analysis identified forty-six flavonoids. Fourteen 17 extracts were tested for their ability to reduce the cytopathic effect (CPE) induced by DENV in Vero 18 cells. UAE extracts of Scutellaria coccinea, Scutellaria incarnata, and Lippia alba contained higher 19 amounts of flavonoid glycosides (from 97.0% to 87.9%) rather than aglycones, and effectively re-20 duced CPE- DENV (IC50: 3.0 to 65 μg/mL; SI: 0.4 to 71). UAE and SFE extracts from L. origanoides 21 with higher content of aglycones (41.7% to 93.4%) than glycosides (0.0 to 58.3%) did not reduce the 22 CPE- DENV. Cluster and one-way ANOVA analyses indicated that strong antiviral effect is associ-23 ated with increased levels of flavone glycosides in the extract. Docking analyses (AutoDock Vina) 24 revealed that flavonoid glycosides exhibited better binding affinity to target proteins (E, Gas6-Axl, 25 clathrin, and dynamin) than aglycones. This study establishes a scientific basis for using extracts 26 rich in flavonoid glycosides, particularly flavones, as starting points for developing plant-based 27 therapies to treat dengue.