Discovery of isoliquiritigenin analogues that reverse acute hepatitis by inhibiting macrophage polarization.

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/ß, 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-1ß both in human and murine cell lines. Subsequent polarization experiments showed SMU-B14 significant reversed the polarization of M1 phenotype primary macrophage activated by Pam3CSK4in 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.

Imidazole Scaffold Based Compounds in the Development of Therapeutic Drugs.

Imidazole has an important five-membered aromatic heterocyclic ring, which is available widely in natural products and synthetic molecules. The special structural characteristics of imidazole ring enable it to bind with a variety of enzymes and receptors through hydrogen bonds, coordination, ion-dipole and cation-π interactions, hydrophobic effects, and Van der Waals forces. These interactions promote several biological activities involving anti-tumor, anti-inflammatory, anti-microbial, and anti-viral properties. Herein, we review and discuss recent developments in using imidazole derivatives and their special pharmacological activities for the treatment of various diseases.

Design, Synthesis, and Structure-Activity Relationship of N-Aryl-N'-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy.

The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1ß from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.