A theoretical study on the structure–activity relationships of metabolites of folates as antioxidants and its implications for rational design of antioxidants Original Research Article

To elucidate the structure–activity relationships of metabolites of folates as antioxidants, the O–H bond dissociation enthalpies (BDEs) and ionization potentials (IPs) for these compounds were calculated by density functional theory (DFT) on B3LYP/6-31+G(,3pd) level. Accordingly, the antioxidant activity difference for metabolites of folates can be elucidated by O–H BDE and IP values and can be further explained in terms of electronic effect and intramolecular hydrogen bond effect of substituents. Furthermore, the potential of the active center of metabolites of folates, 4-hydroxypyrimidine (4-HP), as lead antioxidant, was evaluated by comparing the BDEs and IPs of 4-HP with those of 5-hydroxypyrimidine (5-HP). It was revealed that 4-HP and 5-HP held identical IPs, but the O–H BDE of the former was 22.84 kcal/mol higher than that of the latter, which meant 4-HP was inert in H-atom donation. Nevertheless, the O–H BDE of 4-HP was very sensitive to the substituents, which made NH2-derivatives of 4-HP very active as antioxidants. Therefore, 4-HP is also a potential lead antioxidant and deserves attention in rational design of antioxidants.