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.