Design and synthesis of O-benzoyl amidoxime derivatives as novel TLR2/1 agonists with potent anti-radiation activity in mice.

In this paper, a series of O-benzoyl amidoxime derivatives were designed and synthesized as TLR2/1 small-molecule agonists. Among the target compounds, A-18 exhibited potent activity in human TLR2 and TLR1 transient-cotransfected HEK 293 T cells. Furthermore, we demonstrated that A-18 specifically promotes the formation of TLR2/TLR1 heterodimers and activated the nuclear factor kappa B (NF-κB) signaling pathway. In mice irradiated with 8.5 Gy 60Co γ-ray total body irradiation, prophylactic administration of A-18 achieved a 30-day survival rate of 100%, while A-18 administration post-irradiation still increased the survival rate to 40%. Further studies revealed that A-18 alleviates radiation-induced damage to the small intestine, spleen and thymus, and accelerates the recovery of peripheral blood cells in irradiated mice. Moreover, G-CSF and IL-6, two important cytokines with radioprotective effects, were significantly elevated in the serum of A-18 treated irradiated mice. Therefore, our studies not only discovered A-18, a TLR2/1 small-molecule agonist, as a promising lead compound for the treatment of acute radiation syndrome (ARS) but also demonstrated that TLR2/1 small-molecule agonists can serve as a source of anti-radiation active compounds.