Design of Trehalose‐Based Amide/Sulfonamide C‐type Lectin Receptor Signaling Compounds

Mincle agonists have been shown to induce inflammatory cytokine production, such as tumor necrosis factor‐alpha (TNF) and promote the development of a Th1/Th17 immune response that might be crucial to development of effective vaccination against pathogens such as Mycobacterium tuberculosis . As an expansion of our previous work, a library of 6,6′‐amide and sulfonamide α,α‐ d ‐trehalose compounds with various substituents on the aromatic ring was synthesized efficiently in good to excellent yields. These compounds were evaluated for their ability to activate the human C‐type lectin receptor Mincle by the induction of cytokines from human peripheral blood mononuclear cells. A preliminary structure–activity relationship (SAR) of these novel trehalose diamides and sulfonamides revealed that aryl amide‐linked trehalose compounds demonstrated improved activity and relatively high potency cytokine production compared to the Mincle ligand trehalose dibehenate adjuvant (TDB) and the natural ligand trehalose dimycolate (TDM) inducing dose‐dependent and human‐Mincle‐specific stimulation in a HEK reporter cell line.