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
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.