Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A
Journal article, 2019
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): EC 50 values vary from 0.077 μM 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 non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC 50 50–100 μM, 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.
Tick-borne encephalitis virus
Uracil-1-acetic acid
RAFIs
Enterovirus A
Perylene
Author
Alexey A. Chistov
Russian Academy of Sciences
Alexey A. Orlov
Moscow State University
Russian Academy of Sciences
Philipp P. Streshnev
Russian Academy of Sciences
Nikita A. Slesarchuk
Russian Academy of Sciences
Ilya O. Aparin
Russian Academy of Sciences
Skolkovo Institute of Science and Technology
Brijesh Rathi
University of Delhi
Vladimir A. Brylev
Biotech Industry Ltd
Russian Academy of Sciences
Sergey V. Kutyakov
Russian Academy of Sciences
Irina V. Mikhura
Russian Academy of Sciences
Alexey V. Ustinov
Russian Academy of Sciences
Gunnar Westman
Chalmers, Chemistry and Chemical Engineering, Chemistry and Biochemistry
Vladimir A. Palyulin
Moscow State University
Nidhi Jain
Indian Institute of Technology
Dmitry I. Osolodkin
Moscow State University
Sechenov First Moscow State Medical University
Russian Academy of Sciences
Liubov I. Kozlovskaya
Russian Academy of Sciences
Sechenov First Moscow State Medical University
Vladimir A. Korshun
Russian Academy of Sciences
European Journal of Medicinal Chemistry
0223-5234 (ISSN) 17683254 (eISSN)
Vol. 171 93-103Subject Categories
Biochemistry and Molecular Biology
Medicinal Chemistry
Organic Chemistry
DOI
10.1016/j.ejmech.2019.03.029