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

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

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.

• Language: English
• Keywords: Toll-like receptors, TLR8 antagonists, autoimmune disorders, immunomodulation, pyrimidines
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 159-183
• Numbering: Vol. 75, iss. 2
• PID: 20.500.12556/RUL-169976
• UDC: 616-097
• ISSN on article: 1846-9558
• DOI: 10.2478/acph-2025-0011
• COBISS.SI-ID: 240657155
• Publication date in RUL: 30.06.2025

Record is a part of a journal

• Title: Acta pharmaceutica
• Shortened title: Acta pharm.
• Publisher: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: imunomodulacija, Toll-u podobni receptorji, antagonisti TLR8, avtoimunske motnje