Importance of Lipophilicity for Potent Anti-Herpes Simplex Virus-1 Activity of α-Hydroxytropolones

We previously reported that troponoid compounds profoundly inhibit replication of herpes simplex virus (HSV)-1 and HSV-2 in cell culture, including acyclovir-resistant mutants. Synthesis of 26 alpha-hydroxylated tropolones (αHTs) led to a preliminary structure–activity relationship highlighting the potency of bi-phenyl side chains. Here, we explore the structure–activity relationship in more detail, with a focus on various biaryl and other lipophilic molecules. Along with our prior structure–function analysis, we present a refined structure–activity relationship that reveals the importance of the lipophilicity and nature of the side chain for potent anti-HSV-1 activity in cells. We expect this new information will help guide future optimization of αHTs as HSV antivirals.