Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin

J Med Chem. 2013 Dec 12;56(23):9542-55. doi: 10.1021/jm401604x. Epub 2013 Nov 19.


A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T1/2 values of 1.1-1.2 h (dose of 5 mg/kg i.v.) and MTDs of 60-80 mg/kg (i.p.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Imidazolidines / chemical synthesis*
  • Imidazolidines / pharmacokinetics
  • Imidazolidines / pharmacology
  • Inhibitory Concentration 50
  • Jurkat Cells
  • Lactams / chemical synthesis
  • Lactams / pharmacokinetics
  • Lactams / pharmacology
  • Mice
  • Perforin / antagonists & inhibitors*
  • Pore Forming Cytotoxic Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Imidazolidines
  • Lactams
  • Pore Forming Cytotoxic Proteins
  • perforin, mouse
  • Perforin
  • ethylene urea