Electrochemical and Mechanistic Study of Oxidative Degradation of Favipiravir by Electro-generated Superoxide through Proton-coupled Electron Transfer

22 June 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Electrochemical analyses aided by density functional theory calculations were used to investigate the oxidative degradation of pyrazine antiviral drugs, 3-hydroxypyrazine-2-carboxamide (T-1105) and 6-fluoro-3-hydroxypyrazine-2-carboxamide (favipiravir, T-705), by electro-generated superoxide radical anion. T-1105 and T-705 are antiviral RNA nucleobase analogs that selectively inhibit the RNA-dependent RNA polymerase. They are expected as a drug candidate against various viral infections, including COVID-19. The pyrazine moiety was decomposed by superoxide through proton-coupled electron transfer (PCET). Our results show that its active form, pyrazine-ribofuranosyl-5'-triphosphate, is easily oxidized under inflamed organs by overproduced superoxide through the PCET mechanism in the immune system. This mechanistic study implies that the oxidative degradation of pyrazine derivatives will be prevented by controlling the PCET through simple modification of the pyrazine structure.


superoxide radical anion
proton-coupled electron transfer
density functional theory

Supplementary materials

supporting information
Figure S1, CVs of O2/O2•− in the presence of acidic substrate; CV parameters; Figure S2, in situ Electrolytic UV–Vis (OTTLE) and ESR spectral system; Figure S3, conformers of T-1105 with dGs; Table S1-S4, comparison of dGs for the PCET in dimethyl sulfoxide, acetonitrile, water, and vacuum; Table S5-S6, charge distribution and natural population on the TS structures; Table S7-S8, Calculated geometries of TS.


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