Chalcones as potent tyrosinase inhibitors: the importance of a 2,4-substituted resorcinol moiety.
Compounds, which inhibit tyrosinase, could be effective as depigmenting agents. We have introduced a group of mono-, di-, tri- and tetra-substituted hydroxychalcones as effective tyrosinase inhibitors, showing that the most important factor determining tyrosinase inhibition efficiency is the position of the hydroxyl group(s) rather their number. The aim of the present study was to investigate the contribution of the different functional groups of the tetrahydroxychalcones to their inhibitory potency, with a view to optimizing the design of whitening agents. Four tetrahydroxychalcones were evaluated, the commercially available Butein and other three were synthesized, and their inhibitory effect on tyrosinase was tested. Results showed that a 2,4-substituted resorcinol subunit on ring B contributed the most to inhibitory potency. Changing the resorcinol substitute to position 3,5- or placing it on ring A significantly diminished the inhibitory effect of the compounds. A catechol subunit on ring A acted as a metal chelator (in the presence of copper ions) and as a competitive inhibitor (in the presence of tyrosinase), while a catechol on ring B oxidized to o-quinone (in the presence of both copper ions and tyrosinase). Three of the compounds also demonstrated antioxidant activity, which may contribute to the prevention of pigmentation. An examination of correlations between inhibitory activity and physical properties of the chalcones tested (such as dissociation energy and molecular planarity) showed positive correlation with the moment dipole value in the Y-axis, which may be used as an indicator of the inhibitory potential of new molecules. The present study revealed two very active tyrosinase inhibitors, 2,4,3',4'-hydroxychalcone and 2,4,2',4'-hydroxychalcone (with IC50 of 0.2 and 0.02 microM, respectively). Structure-related activity studies added some understanding of the role and contribution of different functional groups associated with tyrosinase inhibitors.
Khatib
Soliman
S
Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center, PO Box 831, Kiryat Shmona 11016, Israel.
Nerya
Ohad
O
Musa
Ramadan
R
Shmuel
Maayan
M
Tamir
Snait
S
Vaya
Jacob
J
D002478:Cells, Cultured; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002614:Chelating Agents / Q000737:chemistry; D016166:Free Radical Scavengers; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D012118:Resorcinols / Q000494:pharmacology; D013329:Structure-Activity Relationship
D047188:Chalcones; D002614:Chelating Agents; D016166:Free Radical Scavengers; D008543:Melanins; D012118:Resorcinols; D014442:Monophenol Monooxygenase