Anti-inflammatory Activity and Structure-activity Relationships of 2-Hydroxy-N-(alkylphenyl) Nicotinamides

Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of 2-hydroxy-N-(4-substituted phenyl)nicotinamides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. 1 Currently, a series of compounds 5-13, which are alkyl substitution on phenylmoiety, mainly based on 2-hydroxy-N-(phenyl)nicotinamide 4 were further synthesized in high yields. After systematic pharmacological screenings of compounds 5-13, all compounds exhibited less potent anti-inflammatory activity comparable to leflunomide 1 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenan-induced paw edema assay.