Synthesis and structure-activity relationship study of novel quinazolin-4(3H)-one derivatives as toll-like receptor 7 and 8 agonists with immunomodulatory activity

Strašek Benedik, Nika (avtor), Lukić, David (avtor), Slokan, Tjaša (avtor), Dolšak, Ana (avtor), Švajger, Urban (avtor), Kranjc Brezar, Simona (avtor), Talagayev, Valerij (avtor), Wolber, Gerhard (avtor), Čemažar, Maja (avtor), Sosič, Izidor (avtor), Sova, Matej (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: toll-like receptor, TLR7, TLR8, agonist, small-molecule, synthesis, quinazolinone
• 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: 2026
• Št. strani: 24 str.
• Številčenje: Vol. 302, pt. 2, art. 118360
• PID: 20.500.12556/RUL-182775
• UDK: 543.057:616-097
• ISSN pri članku: 1768-3254
• DOI: 10.1016/j.ejmech.2025.118360
• COBISS.SI-ID: 257484035
• Datum objave v RUL: 22.05.2026

Gradivo je del revije

• Naslov: European journal of medicinal chemistry
• Skrajšan naslov: Eur. j. med. chem.
• Založnik: Elsevier
• ISSN: 1768-3254
• COBISS.SI-ID: 23138309

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: receptorji TLR, tolični receptorji, TLR7, TLR8, agonist, molekula majhne velikosti, sinteza, kinazolin, imunski sistem, derivati