Discovery of novel TLR2 antagonists as anti-inflammatory agents

Toll-like receptors (TLRs) were the first identified pattern recognition receptors of the innate immune system. In TLRs family, Toll-like receptor 2 (TLR2) is notable for its extensive expression across various tissues and its ability to recognize a diverse array of pathogenic microorganisms and their products. However, long term or excessive activation of TLR2 can lead to inflammatory, autoimmune disorders and neurodegenerative diseases. Modulation of TLR2 function by small molecules is considered as a promising strategy for the treatment of these diseases. Among the reported TLR2 antagonists, MMG-11, as a selective TLR2 antagonist with low cytotoxicity, can effectively inhibit excessive TLR2 activation and the production of inflammatory factors. However, MMG-11 contained the pyrogallol fragment which reduces the metabolic stability and synthetic accessibility. Meanwhile, the biological activity of MMG-11 needs to be further improved. Herein we designed and synthesized a series of TLR2 antagonists starting from MMG-11 for improving antagonistic activity and metabolic stability. Among thirty tested compounds, T30 exhibited better inhibitory activity and metabolic stability than MMG-11 (T30 IC₅₀ = 11.41 ± 0.83 μM vs MMG-11 IC₅₀ = 22.58 ± 0.97 μM; T30 T_1/2 = 16.67 min vs MMG-11 T_1/2 = 7.88 min). T30 also showed reasonable toxicity profiles and deserved further research.