Green synthesis of biscoumarin derivatives as anti-psoriatic agents targeting PI3K/AKT/JAK2 signaling pathways

Psoriasis is a common chronic inflammatory skin disease. In this work, 20 coumarin derivatives have been synthesized guided by the principles of green chemistry, and their anti-inflammatory effects were assessed both in cellular models and in living organisms. In vitro, the inflammatory activities were determined using RAW264.7 cells, finding that compounds 9 and 15 showed a superior inhibition rate of NO than other compounds. Meanwhile, they could inhibit the detected values of TNF-α, IL-6, and IL-1β. Notably, compound 15 showed better anti-inflammatory activity than compound 9. Moreover, we determined the anti-psoriasis activities using IL-1β-stimulated HaCaT cells and imiquimod (IMQ)-induced mice. Compound 15 reduced the levels of IL-22 and IL-17A in IL-1β-stimulated HaCaT cells in vitro, and the anti-inflammatory effects were assessed in live mice that developed psoriasis-like skin changes following IMQ application. Compound 15 also decreased the levels of IL-17A, IL-23, IL-1β, and IFN-γ, and inhibited the expressions of Ki67 and PCNA. Further, the western blotting and molecular docking analysis showed that compound 15 might ameliorate cutaneous inflammation in psoriasis by targeting the PI3K/AKT/JAK2 signaling route.