Design, synthesis, and biological evaluation of novel glycyrrhetin acylthiourea derivatives as HMGB1 inhibitors for acute kidney injury

A series of glycyrrhetinic acid (GA)-acylthiourea hybrids was developed to address cisplatin-induced acute kidney injury (AKI). Lead 5 f , a glycyrrhetin thiourea-L-alanine conjugate, demonstrated potent nephroprotection (IC 50 = 6.27 μM). In vitro , 5 f (50 μM) reduced cisplatin-induced apoptosis in HK-2 cells (improved Bcl-2/Bax ratio, reduced caspase-3) and suppressed LPS-stimulated inflammation in RAW264.7 cells (TNF-α, IL-6, iNOS, COX-2). Mechanistically, SPR confirmed direct HMGB1 binding ( K d = 123.6 μM), with downstream inhibition of the HMGB1/TLR4/NF-κB pathway (reduced p65 phosphorylation, IκB-α degradation). In vivo , oral 5 f (30/60 mg/kg) attenuated cisplatin-induced AKI in mice, lowering serum biomarkers (Scr, BUN), renal inflammatory cytokines, and histopathological damage. These results established 5 f as a promising therapeutic candidate for cisplatin nephrotoxicity. • Novel glycyrrhetin thiourea-L-alanine conjugate 5 f exhibited potent renoprotection against cisplatin-induced AKI. • 5f binding HMGB1 ( K d = 123.6 μM) suppressed TLR4/NF-κB signaling, reducing TNF-α, IL-6, iNOS, and COX-2 expression. • 5f protected renal tubules and attenuated macrophage-driven inflammation in vivo . • 5f (60 mg/kg) significantly lowered serum creatinine, and tubular necrosis in mice.