Design, synthesis, and anti-inflammatory evaluation of novel analogues derived from the natural product reticuline

The natural alkaloid reticuline exhibits promising anti-inflammatory activity in preclinical models; however, its development is hindered by moderate potency and limited accessibility. To overcome these hurdles, we developed an efficient synthetic route to reticuline, enabling the design and synthesis of 21 structural analogues. Through systematic structure–activity relationship (SAR) exploration, compound 10f was identified as a lead candidate, demonstrating potent anti-inflammatory effects coupled with low cytotoxicity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mechanistic studies revealed that 10f suppressed the production of nitric oxide (NO), reactive oxygen species (ROS), and the pro-inflammatory cytokines TNF-α and IL-6. This anti-inflammatory effect was accompanied by the downregulation of iNOS and COX-2 expression and the inhibition of MAPK signalling pathway. Collectively, this work presents 10f as a promising anti-inflammatory lead compound and provides a rational strategy for the structural optimisation of natural product-inspired scaffolds.