Toll-like receptor 8 (TLR8) belongs to endosomal receptors and has the ability to recognize bacterial and viral single-stranded RNA. This causes the activation of many signalling pathways via adapter proteins, which helps regulating the immune response. From a therapeutic aspect, inhibition of improper activation of these receptors, by host RNA, plays an important role in the treatment of cancer, autoimmune and allergic diseases. Therefore, the subjects of extensive research are precisely the compounds with antagonistic activity on TLR8.
Using molecular modelling, a new generation of TLR8 antagonists was discovered, which is represented by 4-(furan-2-yl)-N-(tyofen-2-ylmetyl)-6-(trifluoromethyl)-pyrimidin-2-amine. Based on its structure, 12 derivatives of 4-(furan-2-yl)-6-(trifluoromethyl)-pyrimidin-2-amine were synthesized, evaluated by various analytical techniques and their biological activity was also determined. Their synthesis took place in four steps. In the first step, a reaction between a ketone and an ester was performed in the presence of a strong base. The resulting 1,3-diketone was then condensed with S-methylisotiourea in the second step of the synthesis. This was followed by oxidation of the sulfide group to the sulfonic group, to which various amines and amino-acid derivatives were introduced via nucleophilic aromatic substitution. The final compounds were then biochemically evaluated to determine their antagonist activity on TLR8 and cytotoxicity.
Based on the relationship between the structure of the compound and its antagonist activity, we found out that the presence of an aromatic ring at the position 2 of the pyrimidine ring plays an important role in the antagonist activity. It fits the TLR8 binding pocket and could form π-π and hydrophobic interactions. The position and nature of a substituent on the benzene ring also play an important role. It must be on the para position to achieve antagonist activity, and the presence of an electron-donor group, which could form hydrogen bonds, increases the potency of antagonist activity.
Compound 16 with a hydroxymethyl group attached to the para position on the aromatic ring proved to be the most potent antagonist. Due to very promising results, the IC50 value of 8,2 µM was also determined for compound 16. Thus, we can confirm that compound 16 represents a great potential for further studies and important step in the development of ingredient drug that could help in the treatment of autoimmune diseases and cancer.
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