Design and synthesis of novel hydroxypyridinone derivatives as potential tyrosinase inhibitors

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3103-3108. doi: 10.1016/j.bmcl.2016.05.006. Epub 2016 May 4.

Abstract

Two groups of novel hydroxypyridinone derivatives 6(a-e) and 12(a-c), were designed as potential tyrosinase inhibitors, and synthesized using kojic acid as a starting material. The tyrosinase inhibitory activity of these two groups was demonstrated to be potent, especially compounds 6e and 12a, whose IC50 values for monophenolase activity were 1.95μM and 2.79μM, respectively. Both of these values are lower than that of kojic acid (IC50=12.50μM). Compounds 6e and 12a were investigated for the inhibitory effect on diphenolase activity. The results showed that the inhibitory mechanism of these two compounds was reversible and that the inhibitory type was a competitive-uncompetitive mixed-type. The values of IC50 of 6e and 12a on the diphenolase activity of tyrosinase were determined to be 8.97μM and 26.20μM, respectively. The inhibitory constants (KI and KIS) of 6e were determined as 17.17μM and 22.09μM, respectively; and the KI and KIS values of 12a were 34.41μM and 79.02μM, respectively. Compound 6e showed a greater ability to reduce copper and a stronger copper chelating ability than kojic acid.

Keywords: 3-Hydroxypyridinone; Inhibitory mechanism; Tyrosinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agaricales / enzymology
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Monophenol Monooxygenase / antagonists & inhibitors*
  • Monophenol Monooxygenase / metabolism
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyridines
  • hydroxypyridines
  • Monophenol Monooxygenase