New 3- and 4-hydroxyfuranones as anti-oxidants and anti-inflammatory agents.

Two series of new furanones substituted by methylsulfonylphenyl or methylsulfamidophenyl moieties were found to protect against oxidation damage by inhibiting or quenching free radicals and reactive oxygen species in in vitro experiments. The effect on lipid peroxidation was also examined. In addition, we investigated the activity of products in two models of inflammation: phorbol ester-induced ear edema in mice and carrageenan-induced paw edema in rat. The most powerful compounds and with reducing activity against DPPH (IC50=1779 and 57 microM, respectively), superoxide anion quenching capacity (IC50=511 and 49 microM, respectively), lipid peroxidation inhibitory effect and anti-inflammatory properties (about 50-65% inhibition of edema at 200 mg/kg ip in both tests used) were selected for further pharmacological and toxicological tests because of their attractive profile for the treatment of inflammatory diseases.

Novel 4,5-diaryl-3-hydroxy-2(5H)-furanones as anti-oxidants and anti-inflammatory agents.

In order to study the effect of phenol moieties on biological activities of ascorbic acid derivatives, we synthesized 13 novel 4,5-diaryl-3-hydroxy-2(5H)-furanones 5a-m with various substitution patterns. Compound 5 g bearing a 2,3-dihydroxy phenyl ring on the 5-position of the heterocycle appeared to be the most powerful anti-oxidant furanone with reducing activity against DPPH (IC(50)=10.3 microM), superoxide anion quenching capacity (IC(50)=0.187 mM) and lipid peroxidation inhibitory effect (IC(50)=0.129 mM). To ascertain determinant molecular features for anti-oxidant activities, structure-activity relationships were studied. Lipophilicity and molecular parameters related to electron distribution and structure (difference in heats of formation between the compound and its radical or its cation radical, energy of the highest occupied molecular orbital, HOMO) were found to correlate with the anti-oxidant action of compounds 5 in the different tests used. Oxygen-derived free radicals are known to contribute to inflammatory disorders; therefore we have investigated effects of compounds 5 in two models of inflammation: phorbol ester-induced ear edema in mice (TPA-test) and carrageenan-induced paw edema in rat. At 100 mg/kg ip in the TPA-test, the anti-inflammatory activity of compounds 5 was potent compared with that of indomethacin and ketorolac and all the results suggested a cyclooxygenase inhibition in the emergence of such properties. The combined pharmacological actions of compounds 5 associated with a favorable therapeutic index prompt with interesting perspectives for their use in heart and brain disorders as well as in inflammatory diseases.