20.500.12556/RUL-184287 Design, synthesis and biological evaluation of novel pyrimidine and quinazoline-based small-molecule Toll-like receptor 8 antagonists Toll-like receptor 8 (TLR8) plays a key role in inflammatory and autoimmune disease pathogenesis. The development of TLR8 antagonists has therefore increased in recent years, however, no clinical candidates have yet reached the market. Here, we report a novel chemotype of selective TLR8 antagonists by replacing isoxazole with pyrimidine in previously reported isoxazole-based antagonists. Guided by an in-house building block library, pyrimidine-based compounds were synthesized and the most potent derivative 16 was biologically characterized. Further optimization via pyrimidine-benzene fusion led to the quinazoline derivative 35, which demonstrated high selectivity and significantly improved low nanomolar potency in inhibiting TLR8-mediated responses, comparable to the most potent antagonist reported to date. Computational and pharmacological studies indicated competitive binding within the chemical ligand-binding pocket at the TLR8 dimerization interface. Favorable physicochemical properties and good metabolic stability make compound 35 a promising lead structure for further chemical optimization into a potent TLR8 antagonist with therapeutic potential. Toll-like receptors TLR8 anti-inflammatory drug discovery pyrimidine quinazoline antagonists Toll-u podobni receptorji TLR8 antagonisti protivnetno delovanje zdravil odkrivanje zdravil pirimidin kinazolin avtoimunske bolezni farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-07-03 08:08:02 2026-07-03 08:08:09 2026-07-04 04:21:55 0000-00-00 00:00:00 2026 0 0 20 str. art. 118822 Vol. 311 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2:616-097 1768-3254 10.1016/j.ejmech.2026.118822 282029059 1-s2.0-S0223523426002679-main.pdf 1-s2.0-S0223523426002679-main.pdf 1 F1ACE381395D1C2103DA315FF4270353 0297ee4d6091f08c0339830d6bf549590d73189c5d7f8049645083d818c2aec7 1d0848a4-76a6-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=236926 https://www.sciencedirect.com/science/article/pii/S0223523426002679 1 75b2dd0f-76a5-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=236925 Fakulteta za farmacijo 0 0 0