Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping

By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC50 = 13.12 +/- 1.03 mu M). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC50 values of 7.46 +/- 1.15 to 48.59 +/- 3.46 mu M, and 8 compounds belonging to two different scaffolds are active to some extent against DENY based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENY.