The tyrosinase inhibitory effects of isoxazolone derivatives with a (Z)-β -phenyl-α, β -unsaturated carbonyl scaffold

Publication date: Available online 31 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Su Jeong Kim, Jungho Yang, Sanggwon Lee, Chaeun Park, Dongwan Kang, Jinia Akter, Sultan Ullah, Yeon-Jeong Kim, Pusoon Chun, Hyung Ryong Moon
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.

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