Benzylidene-linked thiohydantoin derivatives as inhibitors of tyrosinase and melanogenesis: importance of the β-phenyl-α,β-unsaturated carbonyl functionality

Kim, Hye Rim; Lee, Hye Jin; Choi, Yeon Ja; Park, Yun Jung; Woo, Youngwoo; Kim, Seong‐Jin; Park, Min Hi; Lee, Hee Won; Chun, Pusoon; Chung, Hae Young; Moon, Hyung Ryong

doi:10.1039/c4md00171k

Cited by 55 publications

(28 citation statements)

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“…In the present study, we found that the 2,4-dihydroxy functional group on the benzylidene ( 1c ) notably inhibited tyrosinase activity. This inhibitory activity was also previously shown for benzylidene-pyrrolidinedione, benzylidene-thiohydantoin, and benzylidene-thiazolidinedione derivatives as reported by our laboratory [ 25 , 26 , 27 , 28 , 29 , 30 ] inconsistent with in this present study. In addition, our structure–activity relationship data also demonstrated that additional hydroxyl group in the presence of a 4-hydroxy group affect tyrosinase inhibitory activity in a structurally dependent manner ( 1a vs. 1b ; 1a vs. 1c ).…”

Section: Resultssupporting

confidence: 87%

“…Recently, our laboratory discovered and reported several tyrosinase inhibitors [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 29 ]. In particular, Kim et al [ 22 , 23 ] and Lee et al [ 24 ] demonstrated the importance of a thiazolidine derivative bearing 2,4-dihydroxy phenyl moiety (MHY498) which attributed to the inhibitory activity against tyrosinase.…”

Section: Introductionmentioning

confidence: 99%

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A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells

et al. 2018

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In this study, we designed and synthesized eight thiophene chalcone derivatives (1a–h) as tyrosinase inhibitors and evaluated their mushroom tyrosinase inhibitory activities. Of these eight compounds, (E)-3-(2,4-dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (1c) showed strong competitive inhibition activity against mushroom tyrosinase with IC50 values of 0.013 μM for tyrosine hydroxylase and 0.93 μM for dopa oxidase. In addition, we used enzyme kinetics study and docking program to further evaluate the inhibitory mechanism of 1c toward tyrosinase. As an underlying mechanism of 1c mediated anti-melanogenic effect, we investigated the inhibitory activity against melanin contents and cellular tyrosinase in B16F10 melanoma cells. As the results, the enzyme kinetics and docking results supports that 1c highly interacts with tyrosinase residues in the tyrosinase active site and it can directly inhibit tyrosinase as competitive inhibitor. In addition, 1c exhibited dose-dependent inhibitory effects in melanin contents and intracellular tyrosinase on α-MSH and IBMX-induced B16F10 cells. Overall, our results suggested that 1c might be considered potent tyrosinase inhibitor for use in the development of therapeutic agents for diseases associated with hyperpigment disorders.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells

et al. 2018

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“… Chemical structure of inhibitors with β -phenyl- α , β -unsaturated carbonyl functionality, 18a – 18c , 77–80 19a – 19c , 81 20a – 20c , 82 21a – 21b , 83 22a – 22c 85 (a); 23a – 23b 85 and 23c – 23g 88 (b). …”

Section: Mushroom Tyrosinase Inhibitorsmentioning

confidence: 99%

Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors

Pillaiyar

Manickam

Namasivayam

2017

Journal of Enzyme Inhibition and Medicinal Chemistry

676

489

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Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.

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“…Recently we reported that the β-phenyl-α,β-unsaturated carbonyl group is essential for anti-tyrosinase activity. 25 Compounds I–IV ( Figure 1 ), which contain this group, all exhibited good inhibitory activity against mushroom tyrosinase and skin-whitening effects in vivo. 25 – 28 These compounds possess a five-membered ring, and the carbonyl and α-carbon of the β-phenyl-α,β-unsaturated carbonyl group constitute parts of this ring.…”

Section: Introductionmentioning

confidence: 99%

“… 25 Compounds I–IV ( Figure 1 ), which contain this group, all exhibited good inhibitory activity against mushroom tyrosinase and skin-whitening effects in vivo. 25 – 28 These compounds possess a five-membered ring, and the carbonyl and α-carbon of the β-phenyl-α,β-unsaturated carbonyl group constitute parts of this ring. Initially, an expansion of the five-membered ring to a six-membered ring, such as to barbituric acid, was attempted to increase anti-melanogenic efficacy in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and anti-melanogenic effects of (E)-2-benzoyl-3-(substituted phenyl)acrylonitriles

Yun

Kim

Son

et al. 2015

DDDT

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BackgroundTyrosinase is the most prominent target for inhibitors of hyperpigmentation because it plays a critical role in melaninogenesis. Although many tyrosinase inhibitors have been identified, from both natural and synthetic sources, there remains a considerable demand for novel tyrosinase inhibitors that are safer and more effective.Methods(E)-2-Benzoyl-3-(substituted phenyl)acrylonitriles (BPA analogs) with a linear β-phenyl-α,β-unsaturated carbonyl scaffold were designed and synthesized as potential tyrosinase inhibitors. We evaluated their effects on cellular tyrosinase activity and melanin biosynthesis in murine B16F10 melanoma cells and their ability to inhibit mushroom tyrosinase activity.ResultsBPA analogs exhibited inhibitory activity against mushroom tyrosinase. In particular, BPA13 significantly suppressed melanin biosynthesis and inhibited cellular tyrosinase activity in B16F10 cells in a dose-dependent manner. A docking study revealed that BPA13 had higher binding affinity for tyrosinase than kojic acid.ConclusionBPA13, which possesses a linear β-phenyl-α,β-unsaturated carbonyl scaffold, is a potential candidate skin-whitening agent and treatment for diseases associated with hyperpigmentation.

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Benzylidene-linked thiohydantoin derivatives as inhibitors of tyrosinase and melanogenesis: importance of the β-phenyl-α,β-unsaturated carbonyl functionality

Abstract: The “β-phenyl-α,β-unsaturated carbonyl” group might serve as a key pharmacophore for high tyrosinase inhibition.

Cited by 55 publications

References 21 publications

A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells

A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells

Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors

Design, synthesis, and anti-melanogenic effects of (E)-2-benzoyl-3-(substituted phenyl)acrylonitriles

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