Synthesis and PGE2 production inhibition of s-triazine derivatives as a novel scaffold in RAW 264.7 macrophage cells

Abstract

We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE2 reduction at 10μM concentration. Two compounds (7b and 7i) exhibiting >90% inhibition of PGE2 production were found to have IC50 values of 5.76 and 5.52μM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R1=4-Bn-Ph, R2=Cl, R3=Ph, R5=CO2Me) was highly active in cells while maintaining little COX-2 inhibition (∼0% at 10μM). Molecular docking study provides the possibility that compound 7i could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 instead of COX-2 enzyme. Based on this result, our synthetic efforts will focus on intensive structure–activity relationship (SAR) study of s-triazine scaffold to discovery a potential PGE2 synthesis inhibitor.