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. [Display omitted] •A series of novel derivatives of syringaresinol with different scaffolds and pharmacophores were designed and synthesized.•Most derivatives showed significant anti-inflammatory activity. Of these, 7x demonstrated optimal anti-inflammatory activity.•7x has moderate blood-brain barrier permeability and a favorable oral safety profile.•7x possesses significant anti-neuroinflammatory properties via TLR4/NF-κB signaling pathway in vitro and in vivo.•7x exhibits anti-inflammatory activity by promoting the transition from M1-like microglia to M2-like microglia in vivo.