Design and synthesis of 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives as novel tyrosinase inhibitors

被引:89
作者
Ha, Young Mi [1 ]
Park, Yun Jung [2 ]
Kim, Jin-Ah [2 ]
Park, Daeui [1 ]
Park, Ji Young [2 ]
Lee, Hye Jin [2 ]
Lee, Ji Yeon [2 ]
Moon, Hyung Ryong [2 ]
Chung, Hae Young [1 ]
机构
[1] Pusan Natl Univ, Coll Pharm, Mol Inflammat Res Ctr Aging Intervent MRCA, Pusan 609735, South Korea
[2] Pusan Natl Univ, Coll Pharm, Med Chem Lab, Pusan 609735, South Korea
基金
新加坡国家研究基金会;
关键词
Tyrosinase inhibitory activity; 5-(Substituted benzylidene)thiazolidine-2,4-dione derivatives; Docking study with potato catechol oxidase; Antimelanogenesis; CRYSTAL-STRUCTURE; CATECHOL OXIDASE; POTENT; ACID; PIGMENTATION;
D O I
10.1016/j.ejmech.2012.01.019
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In continuing our search for novel tyrosinase inhibitors, a series of 5-(substituted benzylidene)thiazolidine-2,4-diones were rationally designed and synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Twelve target compounds 2a-2l were designed and synthesized based on the structural characteristics of N-phenylthiourea, a tyrosinase inhibitor, and tyrosine and L-DOPA, the natural substrates of tyrosinase. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (2a) and (Z)-5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (2f) exhibited much higher tyrosinase inhibitory activities, with IC50 values of 13.36 and 9.87 mu M, respectively, than kojic acid (IC50 = 24.72 mu M). Kinetic analysis of tyrosinase inhibition revealed that 2a and 2f are competitive inhibitors of mushroom tyrosinase. In addition, through prediction of the potato catechol oxidase tertiary structure and simulation of docking with compounds 2a and 2f using DOCK6, we found that these inhibitors likely bind to the active site of the enzyme. Docking simulation results suggested that 2a and 2f have high binding affinities with potato catechol oxidase. In addition, compounds 2a and 2f effectively inhibited tyrosinase activity and reduced melanin levels in 816 cells treated with alpha-melanocyte-stimulating hormone (alpha-MSH). These data strongly suggest that compounds 2a and 21 suppress the production of melanin via the inhibition of tyrosinase activity. (C) 2012 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:245 / 252
页数:8
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