Synthesis of mitochondria-targeted ferulic acid amide derivatives with antioxidant, anti-inflammatory activities and inducing mitophagy.

ABSTRACT

The seventeen ferulic acid amide derivatives were synthesized by coupling mitochondrial carrier coumarin-3-carboxamide with acrylic acids. The results of cellular antioxidant activity and inhibitory effects on NO production against LPS-stimulated RAW264.7 macrophages indicated four compounds (8c, 8d, 9c, 9d) showed the higher dual-activities of antioxidant and anti-inflammatory. The structure-activity relationship was deduced. In regard to mechanism research, the most potent compound 8d which mainly distributed in mitochondria suppressed the secretion of inflammatory cytokines IL-6 and TNF-α, enhancing mitophagy to alleviate inflammatory response. Besides, the dual-activities were diminished by removal of coumarin carrier in 8d, suggesting the enrichment in mitochondria might be important for activities. This study showed that development of mitochondria-targeted antioxidants could be a feasible strategy to resist inflammation.