Synthesis of mitochondria-targeted caffeic acid-coumarin fluorescent conjugates to ameliorate inflammation in acute lung injury by protecting mitochondria

Antioxidant supplementation demonstrates significant efficacy in alleviating lung inflammation. Herein, the mitochondria-targeted caffeic acid derivatives were designed and synthesized, aimed to improve the symptoms of acute lung injury. By conjugating phenylacrylic acid skeleton with the fluorophore carrier of coumarin-3-carboxamide using ethylenediamine link, fifteen target compounds were obtained. The structure-activity relationships and calculations of Mulliken charges revealed that the installment of electron-withdrawing groups in the α-position of olefinic bond enhanced anti-inflammatory activity. The potential compound 5d containing a catechol fragment and CF₃ group on olefinic bond displayed the highest activities in suppressing the levels of inflammatory factors (NO, TNF-α, IL-6) and attenuating the carrageenan-induced paw edema in rats. Moreover, it localized in mitochondria and protected mitochondria from oxidative and inflammatory insults, including suppressing Reactive Oxygen Species (ROS) level, inhibiting mitochondrial membrane potential collapsing and mitochondrial fragmentation, even enhancing Mitophagy and inhibiting NLRP3 inflammasome activation. In vivo, it significantly attenuated lipopolysaccharide-induced acute lung injury. Our study provides evidence that protection mitochondria by phenolic antioxidant will be a promising approach to relieve inflammation response in the lung.