Structure–activity relationship of dihydroxy-4-methylcoumarins as powerful antioxidants: Correlation between experimental & theoretical data and synergistic effect

The chain-breaking antioxidant activities of eight coumarins [7-hydroxy-4-methylcoumarin ( 1), 5,7-dihydroxy-4-methylcoumarin ( 2), 6,7-dihydroxy-4-methylcoumarin ( 3), 6,7-dihydroxycoumarin ( 4), 7,8-dihydroxy-4-methylcoumarin ( 5), ethyl 2-(7,8-dihydroxy-4-methylcoumar-3-yl)-acetate ( 6), 7,8-diacetoxy-4-methylcoumarin ( 7) and ethyl 2-(7,8-diacetoxy-4-methylcoumar-3-yl)-acetate ( 8)] during bulk lipid autoxidation at 37 °C and 80 °C in concentrations of 0.01–1.0 mM and their radical scavenging activities at 25 °C using TLC–DPPH test have been studied and compared. It has been found that the o-dihydroxycoumarins 3– 6 demonstrated excellent activity as antioxidants and radical scavengers, much better than the m-dihydroxy analogue 2 and the monohydroxycoumarin 1. The substitution at the C-3 position did not have any effect either on the chain-breaking antioxidant activity or on the radical scavenging activity of the 7,8-dihydroxy- and 7,8-diacetoxy-4-methylcoumarins 6 and 8. The comparison with DL-α-tocopherol (TOH), caffeic acid (CA) and p-coumaric acid ( p-CumA) showed that antioxidant efficiency decreases in the following sequence: TOH > CA > 3 > 4 > 6 > 5 > 2 > 1 = 7 = 8 = p-CumA. Theoretical calculations and the “Lipinski’s Rule of Five” were used for explaining the structure–activity relationships and pharmacokinetic behavior. A higher TGSO oxidation stability was observed in the presence of equimolar (1:1) binary mixtures of coumarins with TOH ( 1 + TOH, 3 + TOH and 5 + TOH). However, the synergism (14%) was observed only for the binary mixture of 5 + TOH.