Design and Synthesis of a Potent, Cell Active Purine‐Based Amidoxime Against the Dengue Virus

Abstract

According to WHO, the dengue virus (DENV) is a global health threat and major risk for a pandemic with an estimated 2.5 billion people in more than 100 tropical and subtropical countries at risk of infection. Despite this significant burden, no antiviral drugs are currently approved, thus prompting extensive research efforts pursuing dengue antivirals. Following from our previous work on allosteric inhibitors of the dengue protease, we synthesized novel inhibitors with improved potency and drug‐like characteristics while maintaining the pharmacophore domains of two arylamidoxines and a bromobenzyl substituent. Iterative scaffold hopping and morphing, exemplified purine derivative 4 ( SP‐835G ) with DENV2 EC 50 0.1 µM, CC 50 >100 µM and clogP 3.61. Docking studies support that the corresponding active diamidine SP‐835A shares the same allosteric binding at the dengue protease as our previous hit diamidine SP‐471 . The synthesis of the purine core was optimized to perform at gram scale without need for chromatography including Suzuki–Miyaura cross coupling, Buchwald–Hartwig Ν ‐arylation and nucleophilic aromatic substitution reactions.