Synthesis and nuclear factor-κB inhibitory activities of 6- or 7-methylchroman-2-carboxylic acid N-(substituted) phenylamides

A series of 6- or 7-methylchroman-2-carboxylic acid N-(substituted) phenylamides (2a-s, 3a-s) were synthesized. Their abilities to inhibit nuclear factor-κB (NF-κB) activity were evaluated in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. Compounds with substituents such as -H, -CH₃, and -CF₃ on the phenyl ring were poor inhibitors of NF-κB. The most active NF-κB inhibitors contained 4-Cl (3s) and 4-OMe (3g) in the 7-methylchroman-2-carboxamide derivatives and 2-OH (2b) and 4-Cl (2s) in the 6-methylchroman-2-carboxamide derivatives (IC₅₀: 20.2–24.0 μM). These were slightly more potent than a reference compound, KL-1156 (1) (IC₅₀: 43.9 μM).