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The Tyrosinase Inhibitory Effects of Isoxazolone Derivatives With a (Z)-β-phenyl-α, β-unsaturated Carbonyl Scaffold

The Tyrosinase Inhibitory Effects of Isoxazolone Derivatives With a (Z)-β-phenyl-α, β-unsaturated Carbonyl Scaffold

Su Jeong Kim, Jungho Yang, Sanggwon Lee, Chaeun Park, Dongwan Kang, Jinia Akter, Sultan Ullah, Yeon-Jeong Kim, Pusoon Chun, Hyung Ryong Moon

Bioorg Med Chem. 2018 Aug 7;26(14):3882-3889.

PMID: 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 β-phenyl-α, β-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds 1a-1m, which all possessed the (Z)-β-phenyl-α, β-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)"-β-phenyl-α, β-unsaturated carbonyl scaffold. Compounds 1c and 1m showed greater inhibitory activity than kojic acid: IC50 = 32.08 ± 2.25 μM for 1c; IC50 = 14.62 ± 1.38 μM for 1m; and IC50 = 37.86 ± 2.21 μM 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 (-7.6 kcal/mol) to the active site of tyrosinase with stronger affinity than kojic acid (-5.7 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 β-phenyl-α, β-unsaturated carbonyl scaffold can, like its congener the (E)-isomer, act as an excellent scaffold for tyrosinase inhibition.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP94020	Ethyl benzoylacetate		94-02-0	Price

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