Modification of poorly bioactive sinomenine into more potent immunosuppressive agents by embedding of drug-like fragments

Embedment of drug-like heterocyclic moieties was successfully employed in the novel modification of the readily available but poorly bioactive natural alkaloid sinomenine. Application of the newly proposed approach afforded a number of more potent sinomenine-like molecules with a significantly high hit rate. Among these new analogous, up to 500-fold increase of in vitro immunosuppressive activity was achieved. Further biological experiments of representative compound 4b indicated that it might inhibit NF-κB activation induced by TNF-α in a dose dependent way and showed remarkable in vivo treatment effects against the mouse experimental autoimmune uveoretinitis (EAU) disease models.