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 EC₅₀ 0.066 μM, CC₅₀ > 100 μM and pan-serotype activity (DENV1,3,4 EC₅₀ 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.