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Synthesis and Biological Evaluation of N-Aryl-N’-(5-(2-hydroxybenzoyl) pyrimidin-2-yl)guanidines as Toll-Like Receptor 4 Antagonists

[ Vol. 12 , Issue. 8 ]


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.

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