Background: The diterpenoid alkaloids belong to a highly esteemed group of natural compounds, which display significant biological activities. It is a productive strategy to expand the chemical space of these intriguing natural compounds for drug discovery.Methods: We prepared a series of new derivatives bearing diverse skeletons and functionalities from the diterpenoid alkaloids deltaline and talatisamine based on a diversity-oriented synthesis strategy. The antiinflammatory activity of these derivatives was initially screened and evaluated by the release of nitric oxide (NO), tumor necrosis factor (TNF-alpha), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-activated RAW264.7 cells. Futhermore, the anti-inflammatory activity of the representative derivative 31a was validated in various inflammatory animal models, including phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice ear edema, LPS-stimulated acute kidney injury, and collagen-induced arthritis (CIA).Results: It was found that several derivatives were able to suppress the secretion of NO, TNF-alpha, and IL-6 in LPSactivated RAW264.7 cells. Compound 31a, one of the representative derivatives named as deltanaline, demonstrated the strongest anti-inflammatory effects in LPS-activated macrophages and three different animal models of inflammatory diseases by inhibiting nuclear factor kappa-B (NF-kappa B)/mitogen-activated protein kinase (MAPK) signaling and inducing autophagy.Conclusion: Deltanaline is a new structural compound derived from natural diterpenoid alkaloids, which may serve as a new lead compound for the treatment of inflammatory diseases.