Synthesis of Andrographolide glycosides and evaluation of their antibacterial activity in vitro and in vivo.

Andrographolide, a diterpenoid lactone isolated from Andrographis paniculata, exhibits broad-spectrum biological activities but suffers from poor water solubility and limited oral bioavailability due to its native structure. In recent years, glycosylation has emerged as a promising strategy to improve the pharmacokinetic and pharmacodynamic properties of such compounds. In this study, a series of glycosylated derivatives of 14-deoxy-11,12-didehydroandrographolide, serving as aglycone scaffolds, were systematically synthesized for the first time. Their antibacterial activities were comprehensively evaluated both in vitro and in vivo. The results demonstrated that the antibacterial effect of the glycosylated derivative's parent structure was significantly enhanced. In vivo studies using S. aureus (ATCC 29213) infection rat model further confirmed that compound 5a effectively reduced bacterial burden and pro-inflammatory cytokine levels, potentially through inhibition of the NF-κB signaling pathway. Additionally, blood biochemical indices and histopathological analysis revealed that these derivatives offered protection against organ damage, particularly in lung tissues. Overall, this study highlights glycosylation as an effective approach to optimize andrographolide-based molecules and provides both theoretical support and chemical entities for the development of novel antibacterial glycosides.