This study investigated the gastroprotective efficacy of synthesized
scoparone derivatives on experimentally induced
gastritis and their toxicological safety. Six
scoparone derivatives were synthesized and screened for gastroprotective activities against HCl/
ethanol- and
indomethacin-induced
gastric ulcers in rats. Among these compounds, 5,6,7-trimethoxycoumarin and
6,7,8-trimethoxycoumarin were found to have gastroprotective activity greater than the standard
drug rebamipide; 6-methoxy-7,8-methylenedioxycoumarin, 6-methoxy-7,8-(1-methoxy)-methylenedioxycoumarin, 6,7-methylenedioxycoumarin, and 6,7-(1-methoxy)-methylenedioxycoumarin were found to be equipotent or less potent that of
rebamipide. Pharmacological studies suggest that the presence of a methoxy group at position C-5 or C-8 of the
scoparone's phenyl ring significantly improves gastroprotective activity, whereas the presence of a
dioxolane ring at C-6, C-7, or C-8 was found to have decreased activity. In order to assess toxicological safety, two of the potent gastroprotective
scoparone derivatives-5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin-were examined for their acute toxicity in mice as well as their effect on
cytochrome P450 (CYP)
enzyme activity. These two compounds showed low acute oral toxicity in adult male and female mice, and caused minimal changes to
CYP3A4 and
CYP2C9 enzyme activity. These results indicate that compared to other
scoparone derivatives, 5,6,7-trimethoxycoumarin and
6,7,8-trimethoxycoumarin can improve gastroprotective effects, and they have low toxicity and minimal effects on
drug-metabolizing
enzymes.