20.500.12556/RUL-169976 Optimization of 6-(trifluoromethyl)pyrimidine derivatives as TLR8 antagonists Toll-like receptors (TLRs) are essential for the innate immune system as they recognize pathogen-associated molecular patterns and trigger immune responses. Overactivation of TLR8 by endogenous nucleic acids is associated with the development of autoimmune diseases and promotes inflammatory responses. This study presents the design, synthesis, and evaluation of a series of TLR8 antagonists based on the optimization of previously reported 6-(trifluoromethyl)pyrimidin-2-amines, with targeted modifications to further explore structure-activity relationships (SAR) and increase potency. A two-step synthesis involving nucleophilic aromatic substitution and Suzuki coupling was used to prepare two series of new compounds. The biological evaluation revealed that compounds 14 and 26 exhibited promising TLR8 antagonistic activity with IC$_{50}$ values of 6.5 and 8.7 μmol L$^{-1}$, respectively. Compound 14 showed reduced cell viability at higher concentrations, while compound 26 showed no cytotoxic effects, making it a promising candidate for further investigation. Toll-like receptors TLR8 antagonists autoimmune disorders immunomodulation pyrimidines imunomodulacija Toll-u podobni receptorji antagonisti TLR8 avtoimunske motnje true false true Angleški jezik Slovenski jezik Članek v reviji 2025-06-30 10:48:23 2025-06-30 10:48:28 2025-07-01 03:55:47 0000-00-00 00:00:00 2025 0 0 Str. 159-183 iss. 2 Vol. 75 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-097 1846-9558 10.2478/acph-2025-0011 240657155 15925.pdf 15925.pdf 1 72F50DE7A5EA00C48A634E3E0739ED9B 6884e7abaecc2cc891959309fc19ab71b2af102ad5e8559ff68f9dd869392278 b3feb566-558d-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211860 https://acta.pharmaceutica.farmaceut.org/wp-content/uploads/2025/06/15925.pdf 1 1aa341ce-558d-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211859 Fakulteta za farmacijo 0 0 0