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

• Published in: European journal of medicinal chemistry 2021-08, Vol.220, p.113467-113467, Article 113467
• Main Authors: Kozlovskaya, Liubov I., Volok, Viktor P., Shtro, Anna A., Nikolaeva, Yulia V., Chistov, Alexey A., Matyugina, Elena S., Belyaev, Evgeny S., Jegorov, Artjom V., Snoeck, Robert, Korshun, Vladimir A., Andrei, Graciela, Osolodkin, Dmitry I., Ishmukhametov, Aydar A., Aralov, Andrey V.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Antiviral Agents - toxicity; Antivirals; Cell Line, Tumor; Chlorocebus aethiops; DNA viruses; DNA Viruses - drug effects; Dogs; Humans; Madin Darby Canine Kidney Cells; Microbial Sensitivity Tests; Molecular Structure; Nucleoside analogs; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Nucleosides - toxicity; Oxazines - chemical synthesis; Oxazines - pharmacology; Oxazines - toxicity; Phenoxazine; RNA viruses; SARS-CoV-2; SARS-CoV-2 - drug effects; Structure-Activity Relationship; Vero Cells; Virus Replication - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113467

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. [Display omitted] •8-Alkoxy-substituted, acyclic and carbocyclic phenoxazine derivatives were synthesized.•The activity was assessed against a broad panel of RNA/DNA viruses from 25 species.•Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC50 ≤ 20 μM.•Three of them exhibited submicromolar activity against VZV.•The compounds did not show pronounced cytotoxicity against all the studied cell lines.