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 PGE 2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE 2 reduction at 10 μM concentration. Two compounds ( 7b and 7i ) exhibiting >90% inhibition of PGE 2 production were found to have IC 50 values of 5.76 and 5.52 μM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R 1  = 4-Bn-Ph, R 2  = Cl, R 3  = Ph, R 5  = CO 2 Me) was highly active in cells while maintaining little COX-2 inhibition (∼0% at 10 μM). Molecular docking study provides the possibility that compound 7i could inhibit PGE 2 production by blocking the PGH 2 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 PGE 2 synthesis inhibitor.