Screening a natural product library of 850 compounds yield isoliquiritigenin as an effective anti-inflammatory agent by inhibiting the production of pro-inflammatory NO induced by Pam₃CSK₄, while its activity accompanied by toxicity. Further studies obtained the optimized isoliquiritigenin derivative SMU-B₁₄, which can inhibit Pam₃CSK₄ triggered toll-like receptor 2 (TLR2) signaling with low toxicity and high potency. Preliminary mechanism studies indicated that SMU-B₁₄ worked through TLR2/MyD88, phosphorylation of IKKα/β, leading to the reduce degradation of NF-κB related IKBα and p65 complex, then inhibited the production of inflammatory cytokines, such as TNF-α, IL-6, IL-1β both in human and murine cell lines. Subsequent polarization experiments showed SMU-B₁₄ significant reversed the polarization of M1 phenotype primary macrophage activated by Pam₃CSK₄ in vitro, and reduced the infiltration of neutrophil and polarization of M1-type macrophage, decreased serum alanine transaminase (ALT), as a result protected liver from being injured in vivo. In summary, we obtained an optimized lead compound SMU-B₁₄ and found it functionally blocked TLR2/MyD88/NF-κB signaling pathway to down-regulate the production of inflammatory cytokines resulted significant liver protection property.