title: Synthesis and Biological Evaluation of N-Aryl-N'-(5-(2-hydroxybenzoyl) pyrimidin-2-yl)guanidines as Toll-Like Receptor 4 Antagonists.
abstract: BACKGROUND
  Toll-like receptor 4 (TLR4) has been associated with several inflammatory diseases, such as sepsis, atherosclerosis and chronic pain.
  
  
  OBJECTIVE
  The aim of the present study was to develop an efficient and straightforward synthetic approach for the preparation of small-molecule antagonists Naryl- N'-(5-(2-hydroxybenzoyl)pyrimidin-2-yl)guanidines in order to evaluate these for TLR4 antagonist activity and to obtain useful information about their structure-activity relationships.
  
  
  METHODS
  The present work have designed and optimized a three-step synthetic route for derivatives of a previously demonstrated antagonist of TLR4: 1-(4- fluorophenyl)-2-(5-(2-hydroxy-5-methoxybenzoyl)pyrimidin-2-yl)guanidine. The antagonist activities of eight novel synthesized compounds were evaluated on cells which selectively express TLR4.
  
  
  RESULTS
  Three guanidine derivatives showed promising antagonist activities, with IC50 values in the low micromolar range.
  
  
  CONCLUSIONS
  Our findings represent an important starting point for further studies of small-molecule agents targeting Toll-like receptors.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia. matej.sova@ffa.uni-lj.si.
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.forename: Kaja
authors.initials: K
authors.lastname: Rozman
authors.forename: Urban
authors.initials: U
authors.lastname: Svajger
authors.forename: Primoz
authors.initials: P
authors.lastname: Rozman
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: C000621012:1-(4- fluorophenyl)-2-(5-(2-hydroxy-5-methoxybenzoyl)pyrimidin-2-yl)guanidine; D006146:Guanidines; D011743:Pyrimidines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4