Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, Antivirals, Phenoxazine, Nucleoside analogs, SARS-CoV-2, RNA viruses, DNA viruses, VARICELLA-ZOSTER VIRUS, SELECTIVE-INHIBITION, ANTIVIRAL ACTIVITY, TRICYCLIC ANALOGS, POTENT, REPRODUCTION, ACYCLOVIR, BEARING, MOIETY, Animals, Antiviral Agents, Cell Line, Tumor, Chlorocebus aethiops, DNA Viruses, Dogs, Humans, Madin Darby Canine Kidney Cells, Microbial Sensitivity Tests, Molecular Structure, Nucleosides, Oxazines, Structure-Activity Relationship, Vero Cells, Virus Replication, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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.