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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.
Language:
English
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Slesarchuk N., Khvatov E., Chistov A. et al., Bioorganic and Medicinal Chemistry Letters 2020 Vol. 30 No. 10 Article 127100
Rigid amphipathic fusion inhibitors are potent broad-spectrum antivirals based on the perylene scaffold, usually decorated with a hydrophylic group linked via ethynyl or triazole. We have sequentially simplified these structures by removing sugar moiety, then converting uridine to aniline, then moving to perylenylthiophenecarboxilic acids and to perylenylcarboxylic acid. All these polyaromatic compounds, as well as ...
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Vladimir A. Korshun, RSC advances 2019 Vol. 9 No. 45 P. 26014–26023
The propargylamide of N3-Pom-protected 5-(perylen-3-ylethynyl)uracil acetic acid, a universal precursor, was used in a CuAAC click reaction for the synthesis of several derivatives, including three ramified molecules with high activities against tick-borne encephalitis virus (TBEV). Pentaerythritol-based polyazides were used for the assembly of molecules containing 2/4 antiviral 5-(perylen-3-ylethynyl) uracil scaffolds, the first examples of polyvalent perylene antivirals. Cluster compounds ...
Added: November 8, 2019
Vladimir A. Korshun, European Journal of Medicinal Chemistry 2018 Vol. 155 P. 77–83
series of analogues of potent antiviral perylene nucleoside dUY11 with methylthiomethyl (MTM), azidomethyl (AZM) and HO-C1e4-alkyl-1,2,3-triazol-1,4-diyl groups at 30-O-position as well as the two products of copper-free alkyne-azide cycloaddition of the AZM derivative were prepared and evaluated against tick-borne encephalitis virus (TBEV). Four compounds (4, 6, 8a, 8b) showed EC50 10 nM, thus appearing the most potent TBEV inhibitors ...
Added: November 8, 2019
Rigid amphipathic fusion inhibitors demonstrate antiviral activity against African swine fever virus
Vladimir A. Korshun, Journal of General Virology 2018 Vol. 99 No. 1 P. 148–156
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Most antivirals target viral proteins and are specific for only one virus, or viral type. Whereas viral proteins are encoded in the plastic viral genome, virion lipids are not and their rearrangements during fusion are conserved
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