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 93-103

Subject Categories

Biochemistry and Molecular Biology

Medicinal Chemistry

Organic Chemistry

DOI

10.1016/j.ejmech.2019.03.029

More information

Latest update

5/29/2024