Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study

Abstract Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC 50  = 5700 nM against PGE 2 production), for a potent suppressor of PGE 2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC 50 values of 4.5 and 6.9 nM, respectively, against LPS-induced PGE 2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC 50  = 70 nM) than MK-886 and hit compound 1 , respectively. Molecular docking suggests that compound 8n could inhibit PGE 2 production by blocking the PGH 2 binding site of human mPGES-1 enzyme.