Design, Synthesis, and Evaluation of Baicalein–Thiazole–Piperazine Hybrid As Inhibitor of NF-κB Activation for Hepatobiliary Inflammation Treatment

Chronic inflammation and hepatocellular apoptosis are central features of hepatobiliary disorders, with the NF-κB signaling pathway playing a pivotal regulatory role. In this study, we report the synthesis and biological evaluation of a novel baicalein–thiazole–piperazine hybrid, BTPH-1 (5,6,7-trihydroxy-2-(2-(4-methylpiperazin-1-yl)thiazol-5-yl)-4H-chromen-4-one), designed to enhance anti-inflammatory and hepatoprotective activity. BTPH-1 was synthesized via a condensation–cyclization strategy and its structure was confirmed by spectroscopic analyses. Cytotoxicity assessment in HepG2 cells demonstrated that BTPH-1 was non-toxic at concentrations up to 100 μM. In an LPS-induced hepatocellular inflammation model, treatment with BTPH-1 significantly improved cell viability in a concentration-dependent manner. The compound markedly suppressed the LPS-induced release of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, as determined by ELISA. In addition, BTPH-1 attenuated apoptosis triggered by inflammatory stimulation, indicating a protective effect against hepatocellular injury. Mechanistic investigations using qRT-PCR and Western blot analyses revealed reduced NF-κB p65 expression and enhanced stabilization of IκBα, confirming inhibition of NF-κB activation. Although BTPH-1 exhibited comparatively weaker activity than the standard NF-κB inhibitor BAY 11-7082, it consistently demonstrated significant anti-inflammatory and anti-apoptotic effects. Overall, these findings highlight BTPH-1 as a promising scaffold for the development of therapeutics targeting NF-κB-mediated hepatobiliary inflammatory diseases.