Structure-based design of glycyrrhetinic acid derivatives as potent anti-sepsis agents targeting high-mobility group box-1.

• GA derivatives with fused heterocycles on A ring were structure-based designed and synthesized. • GA-60 could bind to HMGB1. • GA-60 extended survival in LPS/CLP induced mouse models of sepsis. • GA-60 exhibited excellent inhibitory functions on NO, TNF-α, and IL-6. • GA-60 could interfere with MAPKs and NF-κB. Novel Glycyrrhetinic Acid (GA) derivatives with fused heterocycles on A ring were structure-based designed and synthesized. Their potential anti-inflammatory effects were investigated by a classical LPS stimulated macrophage model. Surface plasmon resonance (SPR) was used to verify the binding of GA analogues with HMGB1. A preliminary structure–activity relationship was summarized and an analogue GA-60 with ortho -methoxybenzyl pyrozole showed stronger anti-inflammatory effect and higher affinity for HMGB1 with a K d value of 12.5 μM. In addition, this compound exhibited excellent inhibitory functions on NO (96%), TNF-α (94%), and IL-6 (100%), by interfering with phosphorylation of p38, ERK, JNK MAPKs, as well as that of NF-κB p65 and IKKα/β. Moreover, GA-60 extended the survival of either the classic CLP-induced or LPS-induced sepsis mouse models. Molecular modeling predictions further supported these findings, clearly indicating that inhibiting HMGB1 release, using fused heterocyclic GA derivatives, is a promising strategy for treatment of sepsis. [ABSTRACT FROM AUTHOR]