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

alpha-Hydroxytropolones (alpha HTs) 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 alpha HTs 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 alpha HT-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 alpha HTs. 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 alpha HT antivirals we have found to date. Given the ease of synthesis of amide-appended alpha HTs, this new class of antiviral compounds and the chemistry to make them should be highly valuable in future anti-HSV drug development.