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

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.

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 EC(50) ≤ 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 EC(50) values in low micromolar range, although, accompanied by commensurate cytotoxicity.