Development of novel aminothiazole-comprising 5-LO inhibitors

Future Med Chem. 2016;8(2):149-64. doi: 10.4155/fmc.15.174. Epub 2016 Jan 29.


Background: Leukotrienes are pivotal lipid mediators in various immune and inflammatory reactions. Herein, 5-LO is a validated target. 2-Aminothiazoles, as a privileged structure, implicate known 5-LO inhibitors like ST-1083 (IC50 [polymorphonuclear leukocytes (PMNL)] = 0.68 μM), yet deep structure-activity relationships (SAR) have not been established.

Materials & methods: Compounds were synthesized via Hantzsch thiazole synthesis. Inhibitory activities were evaluated using intact PMNL and purified 5-LO together with cytotoxicity measurements in U937 cells.

Results: We introduced novel functionalities at 2-, 3-, 4- and 5-position of the 2-aminothiazole scaffold and conducted bioisosteric replacement to optimize the parent scaffold. SARs of the 2-aminothiazole scaffold were deduced and extended primarily for inhibition of the 5-LO enzyme.

Conclusion: SAR studies provided at least two optimized leads (ST-1853, ST-1906) with high potency (IC50 [polymorphonuclear leukocytes] = 0.05 μM), specificity and noncytotoxic behavior.

Keywords: 5-lipoxygenase; antileukotriene; cancer; inflammation; lead development; structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 5-Lipoxygenase / chemistry*
  • Arachidonate 5-Lipoxygenase / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Design
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / toxicity
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / toxicity


  • Lipoxygenase Inhibitors
  • Thiazoles
  • 2-aminothiazole
  • Arachidonate 5-Lipoxygenase