Antiviral activity of amide-appended α-hydroxytropolones against herpes simplex virus-1 and -2

Abstract

α-Hydroxytropolones (αHTs) have potent antiviral activity against herpes simplex virus-1 and -2 (HSV-1 and HSV-2) in cell culture, including against acyclovir-resistant mutants, and as a result have the potential to be developed as antiviral drugs targeting these viruses. We recently described a convenient final-step amidation strategy to their synthesis, and this was used to generate 57 amide-substituted αHTs that were tested against hepatitis B virus. The following manuscript describes the evaluation of this library against HSV-1, as well as a subset against HSV-2. The structure-function analysis obtained from these studies demonstrates the importance of lipophilicity and rigidity to αHT-based anti-HSV potency, consistent with our prior work on smaller libraries. We used this information to synthesize and test a targeted library of 4 additional amide-appended αHTs. The most potent of this new series had a 50% effective concentration (EC₅₀) for viral inhibition of 72 nM, on par with the most potent αHT antivirals we have found to date. Given the ease of synthesis of amide-appended αHTs, this new class of antiviral compounds and the chemistry to make them should be highly valuable in future anti-HSV drug development.

Scheme 1. Synthetic routes to ketone and amide-appended αHTs.

Fig. 1. Correlation between lipophilicity and antiviral activity of amide-appended αHTs at (A) 5 μM and (B) 1 μM. Red-shaded points in (A) correspond to 6 molecules shaded and numbered red in (B). Molecules showing no viral suppression but not quantitated (‘−’ in Table 1) are denoted as ‘0’ for graphical purposes.

Fig. 2. HSV replication inhibition at constant concentration. HSV-1 (A) vs. HSV-2 (B) replication inhibition of select αHTs. (C) Inhibition of αHTs and acyclovir (ACV) against wild-type HSV-1 and an acyclovir-resistant mutant (TK−). Data shown are the average and standard deviation of duplicate wells from a representative experiment.