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SUMMARY
Synthesis and Biological Activity of Ethyl 5-(2'-Alkoxycarbonyl substituted phenoxy)furan-2-carboxylate Derivatives
by
Chia-Lin Chang
Graduate Institute of Pharmaceutical Chemistry China Medical College
A series of ethyl 5-(2'-alkoxycarbonyl substituted phenoxy)furan-2-carboxylate derivatives has been synthesized and identified. All of these synthetic compounds were evaluated for antiplatelet aggregation, anti-allergic and anti-inflammatory activities.
In synthesis, CsF promoted the esterification of salicylic acids to give substituted salicylic acid methyl ester (2-4 and 6-13). Ethyl 5-nitro-2-furoate (14) was synthesized by the nitration reaction from ethyl furoate with fuming nitric acid. Ethyl 5-(2'-alkoxycarbonyl substituted phenoxy)furan-2-carboxylates (21-33) were synthesized by the nucleophilic substituted reaction from a mixture of substituted salicylic acid methyl esters and ethyl 5-nitro-2-furoate with sodium hydride. The compounds 21-33 were further hydrolyzed to give 5-(2'-carboxyl substituted phenoxy)furan-2-carboxylic acids (41-48 and 50-53). Then, substituted furo[2,3-b]chromone-2-carboxylic acid ethyl esters (61-68 and 70-73) were synthesized by the cyclization reaction from compounds 41-48 and 50-53 with PPE.
5-(2'-Alkoxycarbonyl substituted phenoxy)furfurals (81-93) were subsequently synthesized by the nucleophilic substituted reaction from a mixture of substituted salicylic acid methyl esters and 5-nitrofurfural with sodium hydride. The compounds 81-93 were further undergone the Knoevenagel reaction to give 5-(2'-alkoxycarbonyl substituted phenoxy)-2-furanacrylic acids (101-109) and 5-(2'-carboxyl substituted phenoxy)-2-furanacrylic acids (111, 113, 117 and 120-123). Then, the compounds 102, 104, 106 and 108 were hydrolyzed to give 5-(2'-carboxyl substituted phenoxy)-2-furanacrylic acids (112, 114, 116 and 118). Finally, the target compounds 21-33, 41-48, 50-53, 61-68, 70-73, 81-93, 101-109, 111-114, 116-118 and 120-123 were evaluated for their antiplatelet aggregation, anti-allergic and anti-inflammatory activities.
The evaluation results of antiplatelet aggregation activitiy showed ethyl 5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32) exhibited a
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significant effect on antiplatelet aggregation. Ethyl 5-(2'-methoxycarbonyl-4'-methylphenoxy)- furan-2-carboxylate (24), ethyl 5-(2'-ethoxycarbonyl-3'-methylphenoxy)furan-2-carboxylate (25), ethyl 5-(2'-methoxycarbonyl-5'-methoxyphenoxy)furan-2-carboxylate (27), ethyl 5-(2'-methoxycarbonyl-4'-methoxyphenoxy)furan-2-carboxylate (28), ethyl 5-(2'-methoxycarbonyl-5'-chlorophenoxy)furan-2-carboxylate (30), ethyl 5-(2'-methoxycarbonyl-4'-chlorophenoxy)furan-2-carboxylate (31) and ethyl 6-bromofuro[2,3-b]chromone-2-carboxylate (72) exhibited moderate effects on
antiplatelet aggregation. Ethyl
5-(2'-methoxycarbonyl-6'-methylphenoxy)furan-2-carboxylate (22), ethyl 5-(2'-methoxycarbonyl-6'-methoxyphenoxy)furan-2-carboxylate (26), ethyl furo[2,3-b]chromone-2-carboxylate (61), ethyl 8-methylfuro-[2,3-b]chromone-2-carboxylate (62), ethyl 6-methylfuro[2,3-b]chromone-2-carboxylate (64), ethyl 6-methoxyfuro[2,3-b]chromone-2-carboxylate (68) and ethyl 6-iodofuro[2,3-b]chromone-2-carboxylate (73) exhibited weak effects on antiplatelet aggregation. The structure-activity relationships of these compounds were examined
and concluded that ethyl
5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32) which bearing a 4'-bromo substituent on benzene ring and ethyl 6-bromofuro[2,3-b]chromone-2-carboxylate (72) which bearing a 6-bromo substituent on ring had the most obvious activity to antiplatelet aggregation effects.
The tested results of anti-allergic activitiy by inhibition test of mast cell degranulation showed ethyl 5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32) exhibited significantly inhibitory effect on compound 48/80-induced mast cell degranulation.
The structure-activity relationships of these compounds were examined and concluded that ethyl 5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32) which bearing a 4'-bromo substituent on benzene ring had the most obvious activity to anti-allergic effects.
The tested results of anti-inflammatory activitiy by inhibition tests of neutrophil degranulation and neutrophil superoxide formation showed ethyl 5-(2'-ethoxy-carbonyl-3'-methylphenoxy)furan-2-carboxylate (25), ethyl 5-(2'-methoxycarbonyl-4'-methoxyphenoxy)furan-2-carboxylate (28) and ethyl 5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32) exhibited significantly inhibitory effects on fMLP-induced neutrophil degranulation. Ethyl 5-(2'-ethoxycarbonyl-3'-methyl-phenoxy)furan-2-carboxylate (25), ethyl 5-(2'-methoxycarbonyl-4'-methoxyphenoxy)-furan-2-carboxylate (28), ethyl
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5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32), 5-(2'-carboxyl-5'-chlorophenoxy)furan-2-carboxylic acid (50), ethyl 6-methylfuro[2,3-b]chromone-2-carboxylate (64), ethyl 6-chlorofuro[2,3-b]-chromone-2-carboxylate (71), 5-(2'-methoxycarbonyl-4'-bromophenoxy)furfural (92) and 5-(2'-methoxycarbonyl-4'-iodophenoxy)furfural (93) exhibited significantly inhibitory effects on fMLP-induced neutrophil superoxide formation. However, none of the compounds inhibited PMA-induced neutrophil superoxide formation. The structure-activity relationships of these compounds were examined and concluded that ethyl 5-(2'-ethoxycarbonyl-3'-methylphenoxy)furan-2-carboxylate (25), ethyl 5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32) and 5-(2'-methoxy-carbonyl-4'-bromophenoxy)furfural (92) which individually bearing a 3'-methyl, 4'-bromo and 4'-bromo substituents on benzene ring and ethyl 6-chlorofuro[2,3-b]-chromone-2-carboxylate (71) which bearing a 6-chloro substituent on ring had the most obvious activity to anti-inflammatory effects.
In addition, they were also evaluated for anti-inflammatory activitiy by inhibition tests of accumulation of nitrite in medium and TNF-α formation in medium. Among the tested results, 5-(2'-methoxycarbonyl-5'-methylphenoxy)-furfural (83), 5-(2'-methoxycarbonyl-4'-methylphenoxy)furfural (84), 5-(2'-methoxy-carbonyl-5'-chlorophenoxy)furfural (90), 5-(2'-methoxycarbonyl-4'-chlorophenoxy)-furfural (91), 5-(2'-methoxycarbonyl-4'-bromophenoxy)furfural (92) and 5-(2'-methoxycarbonyl-4'-iodophenoxy)furfural (93) exhibited significantly inhibitory activity on LPS-induced accumulation of nitrite in medium (Cell line: RAW 264.7 cells). 5-(2'-Methoxycarbonyl-5'-methoxyphenoxy)furan-2-carboxylate (27), ethyl 5-(2'-methoxycarbonyl-4'-methoxyphenoxy)furan-2-carboxylate (28), ethyl 5-(2'-methoxycarbonyl-4'-bromophenoxy)furan-2-carboxylate (32), 5-(2'-methoxycarbonyl-5'-methylphenoxy)furfural (83), 5-(2'-methoxycarbonyl-4'-methylphenoxy)furfural (84), 5-(2'-methoxycarbonyl-5'-methoxyphenoxy)furfural (87), 5-(2'-methoxy-carbonyl-4'-methoxyphenoxy)furfural (88), 5-(2'-methoxycarbonyl-5'-chloro-phenoxy)furfural (90) and 5-(2'-methoxycarbonyl-4'-chlorophenoxy)furfural (91) exhibited significantly inhibitory activity on LPS+IFN-γ-induced accumulation of nitrite in medium (Cell line: N9 cells). 5-(2'-Methoxycarbonylphenoxy)furfural (81), 5-(2'-methoxycarbonyl-5'-methylphenoxy)furfural (83), 5-(2'-methoxycarbonyl-5'-methoxyphenoxy)furfural (87),
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5-(2'-methoxycarbonyl-5'-chlorophenoxy)furfural (90), 5-(2'-methoxycarbonyl-4'-chlorophenoxy)furfural (91), 5-(2'-methoxycarbonyl-4'-bromophenoxy)furfural (92) and 5-(2'-methoxycarbonyl-4'-iodophenoxy)furfural (93) exhibited significantly inhibitory activity on LPS-induced TNF-α formation in medium (Cell line: RAW 264.7 cells).
5-(2'-Methoxycarbonyl-5'-methylphenoxy)- furfural (83), 5-(2'-methoxycarbonyl-4'-methylphenoxy)furfural (84), 5-(2'-methoxy- carbonyl-5'-methoxyphenoxy)furfural (87), 5-(2'-methoxycarbonyl-4'-methoxy- phenoxy)furfural (88), 5-(2'-methoxycarbonyl-5'-chlorophenoxy)furfural (90), 5-(2'-methoxycarbonyl-4'-chlorophenoxy)furfural (91), 5-(2'-methoxycarbonyl-4'-bromo- phenoxy)furfural (92) and 5-(2'-methoxycarbonyl-4'-iodophenoxy)furfural (93) exhibited significantly inhibitory activity on LPS+IFN-γ-induced TNF-α formation in medium (Cell line: N9 cells).
The structure-activity relationships of these compounds were examined and concluded that 5-(2'-methoxycarbonyl-5'-methyl- phenoxy)furfural (83), 5-(2'-methoxycarbonyl-5'-chlorophenoxy)furfural (90) and 5-(2'-methoxycarbonyl-4'-chlorophenoxy)furfural (91) which individually bearing a 5'-methyl, 5'-chloro and 4'-chloro substituents on benzene ring had the most obvious activity to anti-inflammatory effects. The above new findings suggest 5-(2'-methoxy-carbonyl-5'-methylphenoxy)furfural (83), 5-(2'-methoxycarbonyl-5'-chlorophenoxy)-furfural (90) and 5-(2'-methoxycarbonyl-4'-chlorophenoxy)furfural (91) are shown to be new lead compounds with excellent anti-inflammatory activities. The results provide important information for further investigation.
