Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A

European Journal of Medicinal Chemistry. 2019. Vol. 171. P. 93–103.

Vladimir A. Korshun

Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a
nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its
amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to
have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with
remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC50 values vary from
0.077 mM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8
showed even more pronounced activity. All the compounds showed no activity against several nonenveloped
enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of
enterovirus A71 with EC50 50e100 mM, with a non-specific mode of action. The results suggest that the
carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological
activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents
in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity
advocate their potential role in antiviral therapy.

Keywords: Fusion inhibitors, Tick-borne encephalitis virus