Design, synthesis, in vitro, in silico, and SAR studies of flavone analogs towards anti-dengue activity

Flavone has recently been proved as a promising scaffold for the development of a novel drug against dengue fever, one of the major health threats globally. However, the structure-activity relationship study of flavones on the anti-dengue activity remains mostly limited to the natural-occuring analogs. Herein, 27 flavone analogs were successfully synthesized, of which 5 analogs (5e, 5h, 5o, 5q, and 5r) were novel. In total, 33 analogs bearing a diverse range of substituents were evaluated for their efficacy against DENV2-infected LLC/MK2 cells. The introduction of electron-withdrawing groups on ring B such as Br (5m) or NO2 (5n and 5q) enhanced the activity significantly. In particular, the tri-ester 5d and di-ester 5e exhibited low toxicity against normal cell, and exceptional DENV2 inhibition with the EC50 as low as 70 and 68 nM, respectively, which is over 300-fold more active compared to the original baicalein reference. The viral targets for these potent flavone analogs were predicted to be NS5 MTase and NS5 RdRp, as suggested by the likelihood ratios from the molecular docking study. The great binding interaction energy of 8-bromobaicalein (5f) confirms the anti-dengue activity at atomistic level. The physicochemical property of all the synthetic flavone analogs in this study were predicted to be within the acceptable range. Moreover, the QSAR model showed the strong correlation between the anti-dengue activity and the selected molecular descriptors. This study emphasizes the great potential of flavone as a core structure for further development as a novel anti-dengue agent in the future.

Automated summary

Flavone has been identified as a promising scaffold for the development of a novel drug against dengue fever. In this study, 27 flavone analogs were synthesized and evaluated for their efficacy against DENV2-infected cells. The introduction of electron-withdrawing groups on ring B significantly enhanced the activity, with two analogs showing exceptional inhibition of DENV2. Molecular docking study suggested that these potent flavone analogs target NS5 MTase and NS5 RdRp. The physicochemical properties of these analogs were within the acceptable range, and QSAR model showed a strong correlation between the anti-dengue activity and the selected molecular descriptors. This study highlights the great potential of flavone as a core structure for the development of a novel anti-dengue agent.