Investigation of Chiral Imidazoquinoline Based Heterocyclic Small Molecules on TLR7/8 Modulatory Activity

A library of chiral imidazoquinoline derivatives was synthesized and evaluated in HEK-Blue hTLR7 and hTLR8 reporter cell assays. The SAR study led to the identification of a highly potent novel dual TLR7/8 agonist 40 (EC50 78 nM for hTLR7 and 520 nM for hTLR8) and a TLR7/8 antagonist 31 (IC50 270 nM for hTLR7 and 320 nM for hTLR8). The research findings demonstrated the stereochemical dependence of TLR7/8 activity, possibly due to the different interactions of the two enantiomers in the TLR7/8 binding pocket.