Electrochemical and Mechanistic Study of Oxidative Degradation of Favipiravir by Electrogenerated Superoxide through Proton-Coupled Electron Transfer

Abstract

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 the electrogenerated superoxide radical anion (O 2 •– ). T-1105 and T-705 are antiviral RNA nucleobase analogues 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 O 2 •– 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 O 2 •– 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.

Electrochemical and Mechanistic Study of Structure–Activity Relationship of α-, β-, γ-, and δ-Tocopherol on Superoxide Elimination in N,N-Dimethylformamide through Proton-Coupled Electron Transfer

“…In aprotic solvents such as DMF, O2 shows quasi-reversible redox (Equation ( 2)) corresponding to generation of O2 •− in the initial cathodic scan and reoxidation to the starting materials (O2), in the returned anodic scan (1c/1a, solid lines in Figure 2). The reversible CVs investigated here were all modified to irreversible one by the presence of any compounds (a-c, e-h) except (d) δ-TOH with concentration dependency (0 to 5.0, 10.0 × 10 −3 mol dm −3 ), similar to general phenolic compounds [18][19][20][21][25][26][27][28], supporting that CVs of bubbled N2 showed no peak over the potential range. Thus, the loss of reversibility in the CVs of O2/O2 •− is caused by acid-base reaction, the initial PT from the compounds to O2 •− as a Brønsted base forming HO2 • (Equation ( 3)).…”

Electrochemical and Mechanistic Study of Superoxide Scavenging by Pyrogallol in N,N-Dimethylformamide through Proton-Coupled Electron Transfer

“…•− without generating high-energy intermediates, which we refer to as concerted 2PCET reactions, is another feasible pathway [23,28]. For a successful O 2 •− scavenging in either PCET pathway, the second PT coupled to ET is necessary, as reported in our previous studies [25,31]. On the other side, a PCET reaction between PyH 2 − and O 2 •− shown in Figure 6b is also plausible, in case that the initial deprotonation of PyH 3 will partially occur in an aprotic DMF solution.…”

Electrochemical and Mechanistic Study of Superoxide Scavenging by Pyrogallol in N,N-Dimethylformamide through Proton-Coupled Electron Transfer

“…Alternatively, one-step one-electron transfer concerted with sequential two-proton transfer after initial formation of the HB complexes between PyH3 and O2 •− without generating high energy intermediates, which we refer to as concerted 2PCET reactions, is another feasible pathway [23,28]. For a successful O2 •− scavenging in either PCET pathway, the second PT coupled to ET is necessary, as reported in our previous studies [25,31]. On the other side, a PCET reaction between PyH2 − and O2 •− shown in Figure 5b is also plausible, in case that the initial deprotonation of PyH3 will partially occur in an aprotic DMF solution.…”