Optimization of 6-(trifluoromethyl)pyrimidine derivatives as TLR8 antagonists

Strašek Benedik, Nika (avtor), Talagayev, Valerij (avtor), Matziol, Troy (avtor), Dolšak, Ana (avtor), Sosič, Izidor (avtor), Weindl, Günther (avtor), Wolber, Gerhard (avtor), Sova, Matej (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: Toll-like receptors, TLR8 antagonists, autoimmune disorders, immunomodulation, pyrimidines
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: Str. 159-183
• Številčenje: Vol. 75, iss. 2
• PID: 20.500.12556/RUL-169976
• UDK: 616-097
• ISSN pri članku: 1846-9558
• DOI: 10.2478/acph-2025-0011
• COBISS.SI-ID: 240657155
• Datum objave v RUL: 30.06.2025

Gradivo je del revije

• Naslov: Acta pharmaceutica
• Skrajšan naslov: Acta pharm.
• Založnik: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: imunomodulacija, Toll-u podobni receptorji, antagonisti TLR8, avtoimunske motnje