Benzothiazole hydroxy ureas as inhibitors of 5-lipoxygenase: use of the hydroxyurea moiety as a replacement for hydroxamic acid

J Med Chem. 1992 Aug 21;35(17):3180-3. doi: 10.1021/jm00095a012.

Abstract

A novel series of N-[(2-benzothiazolylthio)alkyl]-N'-hydroxyurea derivatives (9-25) was synthesized and evaluated for biological activity as inhibitors of 5-lipoxygenase both in vivo (mouse zymosan peritonitis assay) and in vitro (Ca2+ ionophore-stimulated human peripheral blood leukocyte model). The compounds of this series were based on the corresponding hydroxamic acid derivatives (1, 3, 4, and 5) which were moderately active in vitro but inactive in vivo. A number of compounds in the hydroxyurea series exhibited oral activity for 5-lipoxygenase inhibition. Results of studies relating structure to in vivo and in vitro 5-lipoxygenase activity are reported.

MeSH terms

  • Animals
  • Benzothiazoles
  • Calcimycin / pharmacology
  • Dogs
  • Humans
  • Hydroxamic Acids / chemistry*
  • Hydroxyurea / chemistry*
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Leukotriene B4 / blood
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology
  • Methemoglobin / metabolism
  • Mice
  • Molecular Structure
  • Peritonitis / enzymology
  • SRS-A / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry*

Substances

  • Benzothiazoles
  • Hydroxamic Acids
  • Lipoxygenase Inhibitors
  • SRS-A
  • Thiazoles
  • Leukotriene B4
  • Calcimycin
  • Methemoglobin
  • benzothiazole
  • Hydroxyurea