Bioorganic and Medicinal Chemistry p. 3882 - 3889 (2018)
Update date:2022-08-18
Topics:
Kim, Su Jeong
Yang, Jungho
Lee, Sanggwon
Park, Chaeun
Kang, Dongwan
Akter, Jinia
Ullah, Sultan
Kim, Yeon-Jeong
Chun, Pusoon
Moon, Hyung Ryong
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.
View MoreZhejiang Rongkai Chemical Technology Co.,Ltd.
Contact:+86-578-8185786
Address:Shangjiang Industrial Zone,Suichang
Contact:86-513-84128750/13773795976
Address:No.48.Youyi West Road ,Rudong Development Zone,Jiangsu Province,China
Contact:+86-512-69561895
Address:No.111, Building A4, 218 Xinghu Street, Suzhou Industrial Park, P. R. China
website:http://www.joyochem.com
Contact:0531-82687558, 0531-82687326
Address:Factory Building 11, Jinan Comprehensive free trade zone, Shandong, China
website:http://www.np-chem.com
Contact:0086-25-52346877
Address:199, Jian Ye Road, Nanjing, China
Doi:10.1021/acs.chemmater.8b05143
(2019)Doi:10.1246/bcsj.76.177
(2003)Doi:10.1021/ja01343a004
(1932)Doi:10.1007/BF00629825
(1991)Doi:10.1016/j.tetlet.2004.12.116
(2005)Doi:10.1246/bcsj.81.1675
(2008)