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

Bioorg Med Chem Lett. 2016 Jan 1;26(1):94-9. doi: 10.1016/j.bmcl.2015.11.024. Epub 2015 Nov 10.

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 (IC50=5700nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9nM, 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=70nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme.

Keywords: Inflammation; Molecular docking study; Phenylsulfonyl hydrazide; Prostaglandin E(2); mPGES-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dinoprostone / biosynthesis*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / chemistry
  • Intramolecular Oxidoreductases / metabolism
  • Molecular Docking Simulation*
  • Molecular Structure
  • Prostaglandin-E Synthases
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology*

Substances

  • Enzyme Inhibitors
  • Hydrazines
  • Sulfhydryl Compounds
  • phenylsulfonyl hydrazide
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Dinoprostone