DESIGN AND SYNTHESIS OF SOME P-SUBSTITUTED STYRYLISOXAZOLE CARBOXYLIC ACID DERIVATIVES AS ANTI-INFLAMMATORY AGENTS

Abstract

A series of 5-(p-substitutedstyryl)-isoxazole-3-carboxylic acids (4a-g), carboxylic acid ethyl esters (3a-g) and their corresponding amides (6-29) as well as their hydroxamic acid analogues (5a-g) were synthesized and evaluated for their anti-inflammatory activity. The 1,3dicarbonyl systems 2,4-dioxo-6-arylhex-5-enoic acid ethyl esters (2a-g) were the key intermediate for synthesis of the target isoxazole derivatives. The synthesis of these intermediate was achieved through the reaction of chalcones (1a-g), prepared via aldol condensation of the respective substituted benzaldehyde with acetone in alkaline medium, with diethyloxalate. The purity of the synthesized derivatives was determined by thin layer chromatography (TLC) in addition to the microanalyses and their structures were confirmed by different spectroscopic means. The anti-inflammatory activity of twenty-one compounds [(3a,e,f and g); (4a-g); (5a-g); 22; 24 and 25] were assessed, at a dose of 100 mg/kg, by carrageenan-induced paw edema in rats in comparison to indomethacin as a reference drug. The ulcerogenicity of the compounds 3g, 4g and 5g as representatives of the anti-inflammatory active compounds (ester, carboxylic acid and hydroxamic acid) and indomethacin as reference drug was examined under scan electron microscope, after 24 hours of administration of single dose (100 mg/kg) in rats. Significant anti-inflammatory activity was displayed by most of the target derivatives. p-Nitro and p-methoxystyryl isoxazole carboxylic acid derivatives (4e and 4f) revealed 75% inhibition of inflammation after 1 hr reflected the rapid onset of action of these derivatives, which may sustained up to 5 hr as in case of 4e. The anti-inflammatory activity of 5-(p-nitro and pdimethylaminostyryl)-isoxazole-3-carboxylic acid ethyl esters (3e and 3g) being favorably comparable with indomethacin in terms of potency and ulcerogenic liability. The rational behind the synthesis of these compounds and the structure activity relationship are discussed.