In Vitro and In Silico Studies of Bis-furyl-pyrrolo[3,4-b]pyridin-5-ones on Dengue Virus

A series of six bis-furyl-pyrrolo[3,4-b]pyridin-5-ones synthesized via an Ugi-Zhu reaction coupled to a cascade process [aza Diels-Alder cycloaddition/N-acylation/aromatization] were evaluated in vitro against Dengue virus serotype 4 infection, and the Dengue virus replicon system encoding a Renilla luciferase gen reporter. Also, in silico studies on the non-structural protein 3 (NS3), a flavivirus protease comprising an attractive target for development of therapeutic antivirals bound to non-structural protein 2B (NS3-NS2B) were performed. The in vitro results showed that compounds 1a and 1b reduced the expression of Renilla luciferase in 44.2 and 31.6%, respectively. Additionally, the same compounds decreased viral load, thus revealing their potential activity against Dengue virus serotype 4. From in silico simulations, it was developed a NS3-NS2B model, which was used as a target for the studied molecules. Computational results agree with experimental data, showing that 1a is the best ligand. Finally, a pharmacophoric model was computed for NS3-NS2B, which shows that the ligands need two hydrophobic and one hydrophilic fragment. Such results suggest that two out of the six synthesized bis- furyl-pyrrolo[3,4-b]pyridin-5-ones derivatives presents potential antiviral activity against Dengue virus in vitro.