Synthesis of urea analogues bearing N-alkyl-N'-(thiophen-2-yl) scaffold and evaluation of their innate immune response to toll-like receptors

Eur J Med Chem. 2019 May 1:169:42-52. doi: 10.1016/j.ejmech.2019.02.067. Epub 2019 Mar 1.

Abstract

Previous high throughput virtual screening of 10 million-compound and following cell based validation led to the discovery of a novel, nonlipopeptide-like chemotype ZINC 6662436, as toll-like receptor 2 (TLR2) agonists. In this report, compounds belonging to four areas of structural modification of ZINC6662436 were evaluated for biological activity using human HEK-Blue TLR2 reporter cells, and human THP-1 monocytic cells, yield SMU-C13 as an optimized, direct and high potent (EC50 = 160 nM) agonist of human TLR2. Moreover, preliminary mechanism studies indicated that SMU-C13 through activates TLR1 and TLR2 then stimulates the NF-κB activation to trigger the downstream cytokines, such as TNF-α and secreted alkaline phosphatase (SEAP).

Keywords: Inflammatory; Small molecule antagonist; Toll-like receptor 2 (TLR2); Tumor immunity.

MeSH terms

  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Toll-Like Receptors / antagonists & inhibitors*
  • Toll-Like Receptors / immunology
  • Urea / analogs & derivatives
  • Urea / chemical synthesis
  • Urea / pharmacology*

Substances

  • Thiophenes
  • Toll-Like Receptors
  • Urea