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.
Weber
Valérie
V
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 28, place Henri Dunant, 63001, Clermont-Ferrand Cedex, France.
Coudert
Pascal
P
Rubat
Catherine
C
Duroux
Eliane
E
Vallée-Goyet
Danielle
D
Gardette
Daniel
D
Bria
Marc
M
Albuisson
Eliane
E
Leal
Fernand
F
Gramain
Jean Claude
JC
Couquelet
Jacques
J
Madesclaire
Michel
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D000975:Antioxidants / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy; D005663:Furans / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D005663:Furans