Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane

Dmitry A Vasilenko; Evgenia V Dueva; Liubov I Kozlovskaya; Nikolay A Zefirov; Yuri K Grishin; Gennady M Butov; Vladimir A Palyulin; Tamara S Kuznetsova; Galina G Karganova; Olga N Zefirova; Dmitry I Osolodkin; Elena B Averina

doi:10.1016/j.bioorg.2019.03.028

Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane

Bioorg Chem. 2019 Jun:87:629-637. doi: 10.1016/j.bioorg.2019.03.028. Epub 2019 Mar 16.

Affiliations

¹ Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1 bd. 3, Moscow 119991, Russia.
² Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1 bd. 3, Moscow 119991, Russia; FSBSI "Chumakov FSC R&D IBP RAS", Moscow 108819, Russia.
³ FSBSI "Chumakov FSC R&D IBP RAS", Moscow 108819, Russia; Sechenov First Moscow State Medical University, Moscow 119991, Russia.
⁴ Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1 bd. 3, Moscow 119991, Russia; Institute of Physiologically Active Compounds, Severny Proezd 1, Chernogolovka, Moscow Region 142432, Russia.
⁵ Volgograd State Technical University, Lenina Avenue 28, Volgograd 400005, Russia.
⁶ Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1 bd. 3, Moscow 119991, Russia; FSBSI "Chumakov FSC R&D IBP RAS", Moscow 108819, Russia; Sechenov First Moscow State Medical University, Moscow 119991, Russia. Electronic address: dmitry_o@qsar.chem.msu.ru.
⁷ Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1 bd. 3, Moscow 119991, Russia; Institute of Physiologically Active Compounds, Severny Proezd 1, Chernogolovka, Moscow Region 142432, Russia. Electronic address: elaver@med.chem.msu.ru.

PMID: 30947098
DOI: 10.1016/j.bioorg.2019.03.028

Abstract

Infections caused by flaviviruses pose a huge threat for public health all over the world. The search for therapeutically relevant compounds targeting tick-borne flaviviruses requires the exploration of novel chemotypes. In the present work a large series of novel polyfunctionalized isoxazole derivatives bearing substituents with various steric and electronic effects was obtained by our unique versatile synthetic procedure and their antiviral activity against tick-borne encephalitis, Omsk hemorrhagic fever, and Powassan viruses was studied in vitro. The majority of studied isoxazoles showed activity in low micromolar range. No appreciable cytotoxicity was observed for tested compounds. The lead compounds, 5-aminoisoxazole derivatives containing adamantyl moiety, exhibited strong antiviral activity and excellent therapeutic index.

Keywords: Adamantane derivatives; Aminoisoxazoles; Flavivirus; Omsk hemorrhagic fever virus; Powassan virus; Tick-borne encephalitis virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adamantane / chemistry
Adamantane / pharmacology*
Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Encephalitis Viruses, Tick-Borne / drug effects*
Encephalitis Viruses, Tick-Borne / growth & development
Encephalitis Viruses, Tick-Borne / isolation & purification
Humans
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Swine

Substances

Antiviral Agents
Isoxazoles
Adamantane