Matej Sova, Kaja Rozman, Urban Svajger, Primoz Rozman and Stanislav Gobec Pages 742 - 750 ( 9 )
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.
Conclusion: Our findings represent an important starting point for further studies of small-molecule agents targeting Toll-like receptors.
Formylchromones, pyrimidines, cyanamides, guanidines, microwave-assisted synthesis, Toll-like receptor ligands.
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.