Electrochemical and Mechanistic Study of Superoxide Elimination by Mesalazine through Proton-Coupled Electron Transfer

The elimination of superoxide radical anions (O-2(center dot-)) by 5-amino-2-hydroxybenzoic acid (mesalazine, 5-ASA), 4-amino-2-hydroxybenzoic acid (4-ASA), and related compounds used for ulcerative colitis treatment was investigated using cyclic voltammetry and electron spin resonance (ESR) analyses aided by density functional theory (DFT) calculations. Quasi-reversible O-2/O-2(center dot-) redox was found to be modified by the compounds, suggesting that an acid-base reaction in which a hydroperoxyl radical (HO2 center dot) is formed from O-2(center dot-) occurs. However, the deprotonated 5-ASA anion can eliminate O-2(center dot-) through proton-coupled electron transfer (PCET), forming a radical product. This electron transfer (ET) was confirmed by ESR analysis. The 4-aminophenol moiety in 5-ASA plays an important role in the PCET, involving two proton transfers and one ET based on pi-conjugation. The electrochemical and DFT results indicated that O-2(center dot-) elimination by 5-ASA proceeds efficiently through the PCET mechanism after deprotonation of the 1-carboxyl group. Thus, 5-ASA may act as an anti-inflammatory agent in the alkali intestine through PCET-based O-2(center dot-) elimination.

Automated summary

The study found that compounds like 5-ASA and 4-ASA can efficiently eliminate superoxide radical anions through a proton-coupled electron transfer mechanism, with 5-ASA showing significant effectiveness after deprotonation.