Toll-like receptors (TLRs) represent an important part of innate immunity, which is the first line of defence against any invasion of the human body. Among the ten-known human TLRs, whose function is to recognise pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), TLR8 belongs to the group of endosomal receptors and recognizes viral ssRNA. Upon activation of these receptors, a cascade reaction is triggered that eventually induces gene expression of pro-inflammatory cytokines. If TLR also recognizes the body’s own molecules, which is a characteristic of some autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), it is reasonable to treat the excessive immune response with antagonists.
As a part of this Master’s thesis, using four-step synthetic route, we synthesized 17 final compounds, i.e. new 2-substituted derivatives of 4-(furan-2-yl)-6-(trifluoromethyl) pyrimidine, on the basis of a known TLR8 antagonist, which was previously discovered by virtual screening. The synthesis involved the preparation of a 1,3-dicarbonyl compound, its condensation with S-methylisothiourea to form a pyrimidine ring, the oxidation of sulfide to sulfone, and substitution of selected amine with methylsulfone group at the position 2 of the pyrimidine ring. The identity and purity of the final compounds was confirmed by various analytical techniques. Based on the results of biochemical assays determined for the series of our synthesized compounds new information about TLR8 antagonists’ structure and activity relationship was obtained.
Compound 20 exhibited the most potent antagonist activity. Furthermore, it was found that the hydroxyl group significantly contributes to its potency. In addition, compounds 17-19 also showed weak antagonist activity. All four compounds have in common the substituted benzylamine at position 2, which has a positive effect on the ligand binding due to the possible formation of hydrophobic and π-π interactions.
Compound 20 thus represents a new structural class of TLR8 ligands and an important starting point for further research and development of novel TLR8 antagonists as potential immunosuppressive drugs.