The tyrosinase inhibitory effects of isoxazolone derivatives with a (Z)-ß-phenyl-α, ß-unsaturated carbonyl scaffold.
Bioorg Med Chem
; 26(14): 3882-3889, 2018 08 07.
Article
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| MEDLINE
| ID: mdl-29907470
ABSTRACT
Thirteen (Z)-4-(substituted benzylidene)-3-phenylisoxazol-5(4H)-ones were designed to confirm the geometric effect of the double bond of the ß-phenyl-α, ß-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds 1a-1m, which all possessed the (Z)-ß-phenyl-α, ß-unsaturated carbonyl scaffold, were synthesized using a tandem reaction consisting of an isoxazolone ring formation and a Knoevenagel condensation, and three starting materials, ethyl benzoylacetate, hydroxylamine and benzaldehydes. Some of the compounds showed inhibitory activity against mushroom tyrosinase as potent as compounds containing the "(E)"-ß-phenyl-α, ß-unsaturated carbonyl scaffold. Compounds 1c and 1m showed greater inhibitory activity than kojic acid IC50â¯=â¯32.08⯱â¯2.25⯵M for 1c; IC50â¯=â¯14.62⯱â¯1.38⯵M for 1m; and IC50â¯=â¯37.86⯱â¯2.21⯵M for kojic acid. A kinetic study indicated that 1m inhibited tyrosinase in a competitive manner and that it probably binds to the enzyme's active site. In silico docking simulation supported binding of 1m (-7.6â¯kcal/mol) to the active site of tyrosinase with stronger affinity than kojic acid (-5.7â¯kcal/mol). Similar results were obtained using cell-based assays, and in B16F10 cells, compound 1m dose-dependently inhibited tyrosinase activity and melanogenesis. These results indicate the anti-melanogenic effect of compound 1m is due to the inhibition of tyrosinase and (Z)-isomer of the ß-phenyl-α, ß-unsaturated carbonyl scaffold can, like its congener the (E)-isomer, act as an excellent scaffold for tyrosinase inhibition.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oxazolona
/
Monofenol Monooxigenasa
/
Inhibidores Enzimáticos
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Corea del Sur