Synthetic derivatives of the antifungal drug ciclopirox are active against herpes simplex virus 2.

We previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirteen of these derivative compounds inhibited HSV-2 replication by > 1000- to ∼100,000-fold at 1 µM and displayed EC50 values lower than that of acyclovir, as well as low cytotoxicity, indicating their strong therapeutic potential. Through structural comparison, we also provide evidence for the importance of various structural motifs to the efficacy of ciclopirox and its derivatives, namely hydrophobic groups at R4 and R6 of the ciclopirox core structure. Like ciclopirox, representative analogs exhibit some oral bioavailability but are rapidly cleared in vivo. Together, these results will guide further development of N-hydroxypyridones as HSV therapeutics.

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.

Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile.

Here we describe a rapid and divergent synthetic route toward structurally novel αHTs functionalized with either one or two thioether or sulfonyl appendages. Evaluation of this library against hepatitis B and herpes simplex virus, as well as the pathogenic fungus Cryptococcus neoformans, and a human hepatoblastoma (HepDES19) revealed complementary biological profiles and new lead compounds with sub-micromolar activity against each pathogen.