3'-O-Substituted 5-(perylen-3-ylethynyl)-2'-deoxyuridines as tick-borne encephalitis virus reproduction inhibitors

Gleb V Proskurin; Alexey A Orlov; Vladimir A Brylev; Liubov I Kozlovskaya; Alexey A Chistov; Galina G Karganova; Vladimir A Palyulin; Dmitry I Osolodkin; Vladimir A Korshun; Andrey V Aralov

doi:10.1016/j.ejmech.2018.05.040

3'-O-Substituted 5-(perylen-3-ylethynyl)-2'-deoxyuridines as tick-borne encephalitis virus reproduction inhibitors

Eur J Med Chem. 2018 Jul 15:155:77-83. doi: 10.1016/j.ejmech.2018.05.040. Epub 2018 May 26.

Affiliations

¹ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia.
² Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; Institute of Poliomyelitis and Viral Encephalitides, FSBSI Chumakov FSC R&D IBP RAS, 108819 Moscow, Russia.
³ Institute of Poliomyelitis and Viral Encephalitides, FSBSI Chumakov FSC R&D IBP RAS, 108819 Moscow, Russia; Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
⁴ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; Orekhovich Research Institute of Biomedical Chemistry, 119121 Moscow, Russia.
⁵ Institute of Poliomyelitis and Viral Encephalitides, FSBSI Chumakov FSC R&D IBP RAS, 108819 Moscow, Russia.
⁶ Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
⁷ Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; Institute of Poliomyelitis and Viral Encephalitides, FSBSI Chumakov FSC R&D IBP RAS, 108819 Moscow, Russia; Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
⁸ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia. Electronic address: korshun@ibch.ru.

PMID: 29859999
DOI: 10.1016/j.ejmech.2018.05.040

Abstract

A series of analogues of potent antiviral perylene nucleoside dUY11 with methylthiomethyl (MTM), azidomethyl (AZM) and HO-C_1-4-alkyl-1,2,3-triazol-1,4-diyl groups at 3'-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 to date. Moreover, these nucleosides have higher lipophilicity (clogP) and increased solubility in aq. DMSO vs. parent compound dUY11.

Keywords: Antiviral activity; Cycloaddition; Lipophilicity; Nucleoside; Tick-borne encephalitis virus.

MeSH terms

Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Death / drug effects
Cell Line
Deoxyuridine / chemical synthesis
Deoxyuridine / chemistry
Deoxyuridine / pharmacology*
Dose-Response Relationship, Drug
Encephalitis Viruses, Tick-Borne / drug effects*
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship
Swine
Virus Replication / drug effects

Substances

Antiviral Agents
Deoxyuridine