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 degrees C and 80 degrees C in concentrations of 0.01-1.0 mM and their radical scavenging activities at 25 degrees 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-alpha-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.
Kancheva
Vessela D
VD
Lipid Chemistry Department, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria. vedeka@abv.bg
Saso
Luciano
L
Boranova
Petya V
PV
Khan
Abdullah
A
Saroj
Manju K
MK
Pandey
Mukesh K
MK
Malhotra
Shashwat
S
Nechev
Jordan Z
JZ
Sharma
Sunil K
SK
Prasad
Ashok K
AK
Georgieva
Maya B
MB
Joseph
Carleta
C
DePass
Anthony L
AL
Rastogi
Ramesh C
RC
Parmar
Virinder S
VS
D000975:Antioxidants / Q000737:chemistry*; D003374:Coumarins / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D014468:Umbelliferones / Q000737:chemistry*
C114368:7,8-dihydroxy-4-methylcoumarin; D000975:Antioxidants; D003374:Coumarins; D014468:Umbelliferones; C096882:6,7-dihydroxy-4-methylcoumarin; C506459:5,7-dihydroxy-4-methylcoumarin