Design and synthesis of novel derivatives of bisepoxylignans as potent anti-inflammatory agents involves the modulation of the M1/M2 microglia phenotype via TLR4/NF-κB signaling pathway.

Bisepoxylignans have been reported to possess a variety of biological functions, especially in anti-inflammatory aspects. However, the bis-tetrahydrofuran scaffold restricts the type and position of substituents, which further limits the further optimization of their biological activity and druggability. Here, a series of novel derivative s of bisepoxylignans bearing 7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1H-pyrazolo[3,4-d]pyrimidin-4-amine scaffolds were designed and synthesized by a scaffold hopping strategy. Biological evaluation demonstrated that compound 7x exhibited the most potent anti-inflammatory activity, both in vitro and in vivo. Additionally, 7x displayed an excellent oral safety profile at a dose of 500 mg/kg. The anti-inflammatory effect of 7x is potentially mediated by the inhibition of the TLR4/NF-κB pathway and the promotion of M1 to M2 microglial phenotypic conversion. Taken together, 7x could be a promising lead compound for the development of novel therapeutic agents for the treatment of inflammatory diseases.