Design and synthesis of substituted pyrimidines with potent antiviral activity against dengue

Dengue virus infections affect 2.5 billion people in tropical and subtropical countries and according to WHO it constitutes a major pandemic threat. Dengue remains an unmet medical need as no approved antiviral drugs exist while the two available vaccines have caused safety concerns primarily due to as antibody-dependent enhancement (ADE) associated with the four distinct dengue serotypes. The NS2B/NS3 protease orchestrates key functions in propagating viral replication therefore relevant inhibitors have been pursued extensively yet, their potential has been limited by poor PK properties, cellular activity and pan-serotype efficacy. Following from our pursuit of novel inhibitors that address these aspects, we performed scaffold hopping on our previous protease allosteric inhibitor hit and arrived at pyrimidine derivative 14a ( SP-393D ) with clogP 3.19, demonstrating DENV2 EC 50 0.066 μM, CC 50 >100 μM and pan-serotype activity (DENV1,3,4 EC 50 0.66, 0.071, 1.41 μΜ). Docking studies support that SP-393D binds at the same allosteric pocket of NS2B/NS3 as its predecessor inhibitor but with an additional hydrogen bonding interaction, presumably responsible for the increased potency.