Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study. Issue 1 (1st January 2016) - Kim, Minju
Graphical abstract: Abstract: Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound1 (IC50 = 5700 nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound8n with IC50 values of 4.5 and 6.9 nM, respectively, against LPS-induced PGE2 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 (IC50 = 70 nM) than MK-886 and hit compound1, respectively. Molecular docking suggests that compound8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme.