Phenoxazine nucleoside derivatives with a multiple activity against RNA and DNA viruses

  • Eur J Med Chem. 2021 Aug 5:220:113467. doi: 10.1016/j.ejmech.2021.113467.
Liubov I Kozlovskaya  1 ,  Viktor P Volok  2 ,  Anna A Shtro  3 ,  Yulia V Nikolaeva  3 ,  Alexey A Chistov  4 ,  Elena S Matyugina  5 ,  Evgeny S Belyaev  6 ,  Artjom V Jegorov  4 ,  Robert Snoeck  7 ,  Vladimir A Korshun  4 ,  Graciela Andrei  7 ,  Dmitry I Osolodkin  1 ,  Aydar A Ishmukhametov  1 ,  Andrey V Aralov  8
Affiliations
  • 1. FSBSI "Chumakov FSC R&D IBP RAS", Moscow, 108819, Russia; Institute of Translational Medicine and Biotechnology, Sechenov Moscow State Medical University, Moscow, 119991, Russia.
  • 2. FSBSI "Chumakov FSC R&D IBP RAS", Moscow, 108819, Russia.
  • 3. Smorodintsev Research Institute of Influenza, Saint-Petersburg, 197376, Russia.
  • 4. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
  • 5. Engelhardt Institute of Molecular Biology, Moscow, 119991, Russia.
  • 6. Frumkin Institute of Physical Chemistry and Electrochemistry of the Russian Academy of Science, Moscow, 119071, Russia.
  • 7. Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • 8. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia. Electronic address: [email protected].
PMID: 33894564 DOI: 10.1016/j.ejmech.2021.113467
Abstract

Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus Infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an Antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The Antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC50 ≤ 20 μM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC50 values in low micromolar range, although accompanied by commensurate cytotoxicity.

Keywords
Antivirals; DNA viruses; Nucleoside analogs; Phenoxazine; RNA viruses; SARS-CoV-2.