Design, synthesis, and biological evaluation of glycyrrhetinic acid-cinnamamide derivatives as HMGB1/TLR4 pathway inhibitors for sepsis-induced liver injury.

Sepsis-associated systemic inflammation represents a predominant etiology of acute liver injury, with the high-mobility group box 1(HMGB1)-mediated late-phase inflammatory response playing a central pathogenic role. As a key damage-associated molecular pattern molecule, HMGB1 activates downstream pro-inflammatory cascades through binding to Toll-like receptor 4(TLR4), triggering early-phase cytokine release (TNF-α, IL-1β) and upregulating inflammatory effectors(iNOS, COX-2), thereby establishing a self-amplifying cycle of inflammatory signaling and oxidative stress. Guided by this pathological framework, we developed a series of novel 3-aminoglycyrrhetinic acid derivatives through rational drug design targeting the HMGB1/TLR4 axis. Structural optimization of glycyrrhetinic acid involved C-30 benzyl esterification, C-3 amination, and subsequent conjugation with differentially substituted cinnamic acids, yielding 18 novel analogs. Through systematic pharmacological screening, compound 18 (featuring a 3',4'-dihydroxycinnamamide pharmacophore) emerged as a superior multi-target therapeutic candidate in LPS-challenged RAW264.7 and HepG2 models. It demonstrated concentration-dependent suppression of the upstream mediators TNF-α, IL-1β, HMGB1, and TLR4, while concurrently inhibiting downstream effectors iNOS and COX-2, achieving potent NO reduction (IC