Design and synthesis of forsythin derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) is a clinically high mortality disease, which has not yet been effectively treated. The development of anti -ALI drugs is imminent. ALI can be effectively treated by inhibiting the inflammatory cascade and reducing the inflammatory response in the lung. Forsythia suspense is a common Chinese herbal medicine with significant anti-inflammatory activity. Using forsythin as the parent, 27 Forsythin derivatives were designed and synthesized, and the anti-AIL activity of these compounds was evaluated. Among them, compound B5 has the best activity to inhibit the release of IL-6, and the inhibition rate reaches 91.79% at 25 μM, which was 7.5 times that of the parent forsythin. In addition, most of the compounds have no significant cytotoxicity in vitro. Further studies showed that compound B5 had a concentration-dependent inhibitory effect on NO, IL-6 and TNF-α. And the IC 50 values of compound B5 for NO and IL-6 are 10.88 μM and 4.93 μM, respectively. We also found that B5 could significantly inhibit the expression of some immune-related cytotoxic factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, B5 inhibits NF-κB/MAPK signaling pathway. In vivo experiments showed that B5 could alleviate lung inflammation in LPS-induced ALI mice and inhibit IL-6, TNF-α, COX-2 and iNOS. In summary, B5 has anti-inflammatory effects and alleviates ALI by regulating inflammatory mediators and inhibiting MAPK and NF-κB signaling pathways. [Display omitted] • 27 novel forsythin derivatives from 6 series have been designed and synthesized. • In vitro , compound B5 has the strongest anti-inflammatory activity, with an IC 50 value of 4.93 μM for IL-6. • In vivo , compound B5 can alleviate LPS induced acute lung injury in mice. • Compound B5 alleviates ALI by regulating inflammatory mediators and inhibiting MAPK and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]