Anti-inflammatory Activity and Structure-activity Relationships of N-(Substitued phenyl)-5-methylisoxazole-3-carboxamides

Leflunomide (1) is clinically used for treating rheumatoid arthritis (RA). Study indicated that leflunomide quickly converts non-enzymically into an active metabolite, malononitrilamide (MNA) (2), fully responsible for the both immunosuppressive effects and adverse reactions. We designed a series of 3-isoxazolecarboxamde derivatives in order to diminish the toxicity in physiologic profile by shifting the carbonyl functional group on the isoxazole from the 4-position to the 3-position. Carboxamides 3-9 were synthesized in high yields. After systematic pharmacological screenings of compounds 3-9 including controls, all the compounds exhibited potent anti-inflammatory activity comparable to leflunomide (1), malononitrilamide (2) and even ibuprofen in both in vitro suppressing nitric oxide (NO) and prostaglandin E2 production under the LPS-elicited macrophage Raw 264.7 cells. Among them, N-(4'-hydroxylphenyl)-5-methylisoxazole-3-carboxamides (6) was found most potent.