20.500.12556/RUL-182775 Synthesis and structure-activity relationship study of novel quinazolin-4(3H)-one derivatives as toll-like receptor 7 and 8 agonists with immunomodulatory activity Toll-like receptors (TLRs) 7 and 8 are intracellular pattern recognition receptors that play a crucial role in the innate immune system, making them promising targets for the treatment of viral infections, autoimmune diseases and cancer. In this study, we present the synthesis and biological evaluation of quinazolin-4(3H)-one derivatives as a new class of dual TLR7/8 agonists. In a comprehensive structure-activity relationship (SAR) study, different substitutions on the quinazoline ring and modifications of the aliphatic side chain were investigated. Several compounds showed significantly improved potency compared to the original hit compound, with EC50 values in the nanomolar and low micromolar range for TLR7 and TLR8, respectively. The most potent compounds significantly increased the secretion of the proinflammatory cytokines TNF-α, IL-1β, IL-8 and interferon γ in peripheral blood mononuclear cells (PBMCs). In addition, increased secretion of TNF-α and upregulated CD86 expression in dendritic cells were also observed, indicating their immunomodulatory properties. Notably, the most potent compound 69 significantly suppressed tumor growth in vivo in the CT26 mouse tumor model after intratumoral administration. These results highlight the potential of quinazolinone-based compounds as promising candidates for further development of new immunomodulatory agents targeting TLR7 and TLR8. toll-like receptor TLR7 TLR8 agonist small-molecule synthesis quinazolinone receptorji TLR tolični receptorji TLR7 TLR8 agonist molekula majhne velikosti sinteza kinazolin imunski sistem derivati true false true Angleški jezik Slovenski jezik Članek v reviji 2026-05-22 12:36:01 2026-05-22 12:36:10 2026-05-23 04:42:00 0000-00-00 00:00:00 2026 0 0 24 str. pt. 2, art. 118360 Vol. 302 Jan. 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 543.057:616-097 1768-3254 10.1016/j.ejmech.2025.118360 257484035 1-s2.0-S0223523425011250-main.pdf 1-s2.0-S0223523425011250-main.pdf 1 7C7A0EAB65E05905BE3AB5FF0290CCBA b362af6467c46d36a93a5d61c1683da24609fbf739151b86f25cc70ba30cbb20 856c0611-55ca-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=234310 https://www.sciencedirect.com/science/article/pii/S0223523425011250 1 bb18beee-55c9-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=234309 Fakulteta za farmacijo 0 0 0